Topic

Health, Fitness Subtopic

& Nutrition Nutrition

Gut Health Explained

Course Guidebook
Gabrielle Fundaro, PhD
Copyright © The Teaching Company, 2024

Printed in the United States of America

This book is in copyright. All rights reserved.

Without limiting the rights under copyright reserved above,

no part of this publication may be reproduced, stored in or
introduced into a retrieval system, or transmitted, in any
form, or by any means (electronic, mechanical, photocopying,
recording, or otherwise), without the prior written permission
of The Teaching Company.

4840 Westfields Boulevard, Suite 400

Chantilly, VA 20151‑2299
USA
1-800-832-2412
www.thegreatcourses.com
Gabrielle Fundaro
Gabrielle Fundaro is an ACE-Certified Health Coach trained in motivational
interviewing, sports nutrition, and the Monash Low FODMAP program. She
holds a PhD in Human Nutrition, Foods, and Exercise from Virginia Tech.
Before launching her telehealth coaching business, Vitamin PhD Nutrition,
she was an Assistant Professor of Exercise Science at Georgia Gwinnett
College. She has spoken internationally on gut health and behavior change
and has contributed to magazines such as Shape, Oxygen, and Reader’s Digest.
She is the coauthor of The Science of Gut Health: What the Research Really Says
about Your Gut Microbiome.
i
Table of Contents

About Gabrielle Fundaro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i

Disclaimer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii
1. What Is Gut Health? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2. Introducing the Gut Microbiome . . . . . . . . . . . . . . . . . . . . . . . 9
3. How Researchers Study the Gut Microbiome . . . . . . . . . 18
4. How to Spot Gut Health Pseudoscience . . . . . . . . . . . . . . 25
5. The Microbiome and Gastrointestinal Disease . . . . . . . . . 34
6. The Microbiome and Immunity . . . . . . . . . . . . . . . . . . . . . . . 41
7. The Microbiome and Metabolic Health . . . . . . . . . . . . . . . . 49
8. The Gut-Muscle Axis and Exercise . . . . . . . . . . . . . . . . . . . . 56
9. The Gut-Brain Axis and Mood . . . . . . . . . . . . . . . . . . . . . . . . 64
10. Common Digestive Complaints . . . . . . . . . . . . . . . . . . . . . . . 72
11. Eating for Gut Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
12. A Lifestyle for Gut Health . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

ii
Disclaimer
This content is intended to convey general health, fitness, and nutritional
information and is for educational purposes only. It is not a substitute for, nor
does it replace, professional medical advice, diagnosis, or treatment of health
conditions. Please consult your physician or other health-care professional
before beginning or changing any fitness or nutrition program to make sure
that it is appropriate for your needs.

If you have any concerns or questions about your health, you should always
consult a physician or other health-care professional. Do not disregard,
avoid, or delay obtaining medical or health-related advice from your health-
care professional because of something you may have seen or heard in this
content. Current health and fitness research may exist that could affect the
educational information provided in this content, and advice found herein
may not be based on the most recent findings or developments. Therefore,
the use of any information provided in this content is solely at your own risk.
By continuing with the programs, exercises, advice, information, and/or diets
discussed in this content, you recognize that there are risks of injury or illness
that can occur because of your use of the aforementioned information, and
you expressly assume such risks and waive, relinquish, and release any claim
that you may have against The Teaching Company as a result of any future
physical injury or illness incurred in connection with, or as a result of, use or
misuse of the programs, exercises, advice, information, and/or diets discussed
in this content. The opinions and positions provided in this content reflect
the opinions and positions of the relevant presenter and do not necessarily
reflect the opinions or positions of The Teaching Company or its affiliates.

The Teaching Company expressly DISCLAIMS LIABILITY for any DIRECT,

INDIRECT, INCIDENTAL, SPECIAL, OR CONSEQUENTIAL
DAMAGES OR LOST PROFITS that result directly or indirectly from the use
of this content. In states that do not allow some or all of the above limitations
of liability, liability shall be limited to the greatest extent allowed by law.

iii
What Is Gut Health? 1
Inside your body right now, a community of
microscopic organisms is living, reproducing,
changing, and communicating with the rest of your
body. This population of microbes that resides
along the length of your digestive tract is called
the gut microbiome. Within the last 20 years,
researchers have found that, from digestion and
metabolism to immune defense and even brain
activity, these microbes play integral roles in
human development, health, and disease from birth
until death. As you’ll learn throughout this course,
the field of gut microbiome science is rife with
opportunity, excitement, and hope for new ways
to predict, diagnose, and even cure diseases—but
it’s also fertile soil for pseudoscience, exaggeration,
extrapolation, and unscrupulous marketing.

1
 1. What Is Gut Health?

Gut Health
What is gut health? This is one of the most important questions in
microbiome science. Many researchers believe it may be impossible to
define a healthy gut microbiome given the dizzying number of factors that
influence the microbial community. This makes “healthy” too subjective to
be meaningful. However, you can still talk about gut health in a meaningful
way because, over the last decade, researchers have collected more evidence
to support the idea that the gut microbiome plays an important role in both
health and disease. Simultaneously, it’s important to clear up some of the
poorly defined ideas that have clouded this conversation and often led to
exaggeration, misunderstanding, and the dissemination of flat-out falsehoods.

2
 1. What Is Gut Health?

Gut microbiome publications are plagued by the use of poorly defined

terms to explain their findings, which could threaten the progress of
gut microbiome science. For example, when researchers describe the gut
microbiome using terms like balanced or imbalanced and eubiosis or dysbiosis,
they’re perpetuating old and somewhat unscientific beliefs about how the
human body works. These kinds of broad, catchall explanations for how the
gut microbiome works have a tendency to gain popularity.

Take the word imbalance. It’s a poorly defined term that nonetheless feels like
it could explain all kinds of ailments. And it’s a brilliant marketing tool: “If
only there were a product that could fix the imbalance of my gut microbiome,
then I could be healthier.” Without a way to define a healthy gut microbiome,
you have no way to determine what types of changes might be unhealthy in
comparison or—importantly—why they’re unhealthy. So, when influencers
and popular media use the term gut health, they’re building on the ambiguity
of these definitions. They also tend to assume that changes in the microbiome
can cause specific health outcomes (for example, introduce a microbe or
prevent a disease) even though the evidence doesn’t support this assumption.
Keeping this in mind, a more satisfying answer has been developed, which
you can call the three Ds of gut health.

The Three Ds
The first D stands for disease. Here, this refers to the presence or absence of
disease in the digestive tract. About 40% of people globally are suffering from
a gastrointestinal (GI) disease.

The second of the three Ds is digestion. This encompasses both the subjective
experience of digestion, like nausea, bloating, gas, and stool quality, and
the objective ability of your GI tract to effectively break down and absorb
nutrients. For example, you might feel some gas and bloating after eating
certain foods (subjective experience), but your intestinal tract is functioning
normally (objective ability).

3
 1. What Is Gut Health?

The third D is diversity, or the variety and proportions of microbes that

inhabit the digestive tract. Diversity is often used to describe the richness
of microbial species in the gut—that is, the number of different types of
microbes—as well as the evenness, or the proportions, of microbes and how
they’re distributed. Diversity can also measure the variety of genes these
microbes have. The number and proportions of the microbes, or taxonomic
diversity, tells you only one part of the story. You need to know the functional
diversity, or the variety of genes, to know what those microbes are capable
of doing.

Functional and Organic Diseases

How can researchers evaluate—or even establish—the complete well-
being of an entire organ system populated by trillions of living organisms?
There isn’t a clear answer to that question yet, but it might be easiest to
start by determining the presence or absence of a GI disease and how it
affects digestion. GI diseases can be organized generally into two categories:
functional and organic.

4
 1. What Is Gut Health?

A functional disease only affects the way the GI tract works, without any
damage to the tissues. Irritable bowel syndrome (IBS) is a common example.
Although the intestinal tract looks healthy, it doesn’t function properly, so
people with IBS will still experience some uncomfortable symptoms like
abdominal pain and irregular bowel habits. Meanwhile, inflammatory bowel
disease (IBD) is an organic disease because it affects both the tissues and the
function of the GI tract. IBD can cause ulcers to form in the intestinal lining,
which impair nutrient absorption and can put a person’s life at risk if an
infection forms.

Some diseases, like infectious diarrhea, can be cured, but others, like IBS
or IBD, are incurable and need to be managed. GI diseases can be managed
in a number of ways. Lifestyle changes like exercising regularly and getting
adequate sleep can help manage some symptoms of GI diseases, while in other
cases, prescription medications are required.

“Balanced” and “Imbalanced”

The digestion aspect of gut health is obviously linked to the disease aspect,
and both digestion and disease are related to microbiome diversity in ways
researchers are just beginning to understand. Unlike digestion and disease,
a “healthy” level of diversity can’t be defined yet. The idea that a healthy
microbiome is a balanced one is based on ancient beliefs that have since been
debunked.

In ancient Greece, doctors thought that illness was caused by an imbalance of

the four humors in the body: blood, phlegm, black bile, and yellow bile. They
believed that digestion produced these humors and that it was the physician’s
job to correct imbalances. Today, when it comes to the gut microbiome,
balance is still a buzzword.

Without any real parameters to evaluate the healthiness of someone’s

microbiome, many researchers and media outlets use subjective terms like
balanced or imbalanced, which imply health or dysfunction, respectively.
These ideas have led to the assumption that a healthy person will also have a
healthy gut microbiome, so whatever the composition is, it must be balanced,
or in a state of eubiosis. A person with a disease, however, must have an

5
 1. What Is Gut Health?

imbalanced microbiome, or dysbiosis. In other words, a healthy person has

the “right” amount of microbial diversity, while an unhealthy person has the
“wrong” amount.

To assert that someone’s microbiome is actually imbalanced, you need some

sort of reference for what you’d expect to see in a balanced community. But
just because one healthy person’s microbiome looks a certain way, you can’t
assume that all microbiomes should look that way. Plenty of healthy people
have vastly different microbiomes. What researchers have actually observed is
simply a difference in microbial communities, and they don’t know enough
yet to say that it’s a “bad” difference.

Benefits of Microbial Diversity

You may have seen recent gut health tests claiming to provide information
about your level of dysbiosis, with reference ranges to indicate whether
microbes are higher or lower than they “should” be. Unfortunately, far from
being based on clinically validated data, these reference ranges are based on
the cohorts, or the people who were chosen by the test’s development team.
So, you could be labeled as having dysbiosis because your microbiome differed
from the microbiome of a healthy person, without any real scientific evidence
to support the notion that you’re the one with dysbiosis and not the healthy
person used to develop the reference ranges.

However, even if researchers don’t know what microbes or proportions lead

to better health, they can still get an inkling, from experimental data, about
how microbes interact with one another in ways that could affect their human
hosts. Fecal transplants in rodents, for example, have revealed a relationship
between body weight and certain microbes that cohabitate the gut.

Researchers Buck S. Samuel and Jeffrey I. Gordon, along with colleagues,

wanted to know the digestive impact of a particular archaeon commonly
found in our colon, Methanobrevibacter smithii. Using fecal transplant,
they gave rodents another microbe that forages the polysaccharides in our
diet, Bacteroides thetaiotaomicron, which they introduced with or without
the microbe of interest, M. smithii. They found that animals who were
co-colonized with both of these microbes exhibited significant increases in

6
 1. What Is Gut Health?

weight gain and fatty tissue—compared to animals colonized with just B.

thetaiotaomicron alone or those co-colonized with a microbe that was not M.
smithii. Although M. smithii might seem insignificant based on its extremely
low abundance relative to other microbes, it makes the process of microbial
fermentation more efficient by recycling the end product, hydrogen, to create
methane.

However, while studies like these are helpful for identifying certain
community dynamics or cell signaling pathways, it’s still unclear exactly
how changes in gut microbiome diversity translate to changes in the health
or disease of the host. This study and others like it confirm that both
taxonomic and functional diversity need to be considered to understand how
the microbiome might affect your health. Researchers need to look at both
the variety of microbes and what they’re actually doing—how they interact
with each other and the host. The hope is that future studies will be able to
establish clinical markers for disease as it relates to the gut microbiome.

Researchers have also begun to identify relationships between microbial

diversity and healthy lifestyle habits like exercising and eating a prudent diet.
While the mechanisms are still unclear, there’s enough consistent evidence to
notice some patterns. For example, several observational studies have found
that long-term dietary patterns have a more significant and lasting impact on
the gut microbiome than short-term interventions. These long-term dietary
patterns also happen to modify your risk of certain diseases. A Mediterranean
diet could reduce your risk of colorectal cancer by about 20%, and it’s
also associated with a more diverse microbiome compared to a standard
American diet.

Exercise plays a role, too. If you’re physically fit and exercise regularly, you’ll
probably have a more diverse microbiome than a sedentary person, with
specific enrichment of microbes that produce beneficial short-chain fatty
acids (SCFAs). Some elite athletes have unusually high levels of microbes that
specialize in converting metabolic leftovers into useful energy sources for their
human hosts, for example. It’s still unclear whether these microbes contribute
directly to exercise performance or health, but some research suggests that
dietary patterns can dictate whether an active person’s microbiome will be
more diverse than that of a sedentary person.

7
 1. What Is Gut Health?

So, the take-home message is simply to try eating a prudent diet while
exercising regularly to maximize the potential benefits of either habit.
Researchers are not yet able to quantify how much or what kind of diversity
we need to optimize health. But the appropriate amount—whatever that may
be for a person—creates a resilient microbial ecosystem that fulfills all of its
functions, like immune defense and energy harvesting, and bounces back
from perturbations, like antibiotics or infections.

READING
Durk, R. P., E. Castillo, L. Márquez-Magaña, G. J. Grosicki, N. D. Bolter, C. M. Lee, and
J. R. Bagley. “Gut Microbiota Composition Is Related to Cardiorespiratory Fitness in
Healthy Young Adults.” International Journal of Sport Nutrition and Exercise Metabolism
29, no. 3 (2019): 249–253. https://doi.org/10.1123/ijsnem.2018-0024.

Garcia-Larsen, V., V. Morton, T. Norat, A. Moreira, J. F. Potts, T. Reeves, and

I. Bakolis. “Dietary Patterns Derived from Principal Component Analysis
(PCA) and Risk of Colorectal Cancer: A Systematic Review and Meta-
Analysis.” European Journal of Clinical Nutrition 73, no. 3 (2019): 366–386.
https://doi.org/10.1038/s41430-018-0234-7.

Hooks, K. B., M. A. O’Malley. “Dysbiosis and Its Discontents.” mBio 8, no. 5 (2017).
https://doi.org/10.1128/mBio.01492-17.

Jang, L. G., G. Choi, S. W. Kim, B. Y. Kim, S. Lee, and H. Park. “The Combination of
Sport and Sport-Specific Diet Is Associated with Characteristics of Gut Microbiota: An
Observational Study.” Journal of the International Society of Sports Nutrition 16, no. 1
(2019): 21. https://doi.org/10.1186/s12970-019-0290-y.

Loughman, A., and H. M. Staudacher. “Treating the Individual with Diet: Is Gut
Microbiome Testing the Answer?” The Lancet Gastroenterology & Hepatology 5, no. 5
(2020): 437. https://doi.org/10.1016/S2468-1253(20)30023-6.

McBurney, M. I., C. Davis, C. M. Fraser, B. O. Schneeman, C. Huttenhower, K. Verbeke,

J. Walter, and M. E. Latulippe. “Establishing What Constitutes a Healthy Human Gut
Microbiome: State of the Science, Regulatory Considerations, and Future Directions.”
Journal of Nutrition 149, no. 11 (2019): 1882–1895. https://doi.org/10.1093/jn/nxz154.

Olesen, S. W., and E. J. Alm. “Dysbiosis Is Not an Answer.” Nature Microbiology 1 (2016):
1–2. https://doi.org/10.1038/nmicrobiol.2016.228.

8
Introducing the
Gut Microbiome
2
Your cardiovascular, immune, nervous, and
endocrine systems are all influenced by your gut
microbes. The microbiota can produce useful
compounds that nourish intestinal cells, support
metabolic health, protect against certain types
of cancer, modify the immune system, and even
influence brain activity. Gut microbes can also
harvest energy from the diet by converting
indigestible fibers into fatty acids that your cells
can utilize. In this lecture, you’ll get to know your
gut microbes a bit better. You’ll start by exploring
the digestive tract to see how this landscape
shapes the microbial community. Then, you’ll learn
how you acquired your personal set of microbes
and the many factors that create a microbiome as
unique as your fingerprints.

9
 2. Introducing the Gut Microbiome

The Digestive Tract

Gut is a term used to describe the GI or digestive tract, which includes the
mouth, esophagus, stomach, small and large intestines, rectum, and anus.
The liver, gallbladder, pancreas, and salivary glands are considered accessory
organs. The variability of the pH, anatomy, oxygen, and nutrient availability
along the GI tract provides a variety of microhabitats where microbes compete
for access to resources. Because microbes interact with each other while
responding to environmental changes, the growth of one group may inhibit or
promote the proliferation of another. This leads to the distinct biogeography,
or geographical distribution, of microbes throughout the intestine.

The upper GI tract consists of the mouth, esophagus, stomach, and the first
part of the small intestine (or the duodenum). Mastication, or chewing,
breaks your meal down into smaller pieces that mix with the solution of water
and digestive enzymes in your saliva. After passing through the esophagus,
you come to the stomach—an expansive reservoir that can temporarily stretch
enough to accommodate anywhere from 50 milliliters up to 2 liters. As it
churns, food is mixed with the 1 to 3 liters of gastric juices it produces each
day. It maintains an impressively acidic pH of about 1 to 2, which serves two
functions: breaking down food and providing an initial line of defense against
potential pathogens. Between the extreme acidity and the high oxygen levels,
many pathogenic bacteria won’t survive transit through the stomach.

The lower GI tract includes the small and large intestines, which are long,
fleshy tubes. Your abdominal cavity is packed with 22 feet of small intestine
and 5 feet of large intestine. The entire lower GI tract is surrounded by layers
of smooth muscle called the muscularis externa, which contract to mix food
with digestive enzymes and push it along, like a conveyor belt in a factory.
The intestines are the main site of digestion and absorption, so they’re lined
with specialized cells that produce digestive enzymes and absorb nutrients.
The cells of the small intestine are covered with a thin layer of protective
mucus, but in the large intestine, they are covered by two thick layers of
mucus. The uppermost layer serves as a shelter and nutrient source for
certain microbes, while others prefer to exist in the lumen, the cavity of the
intestine itself.

10
 2. Introducing the Gut Microbiome

The gut contains an estimated 70% of your immune tissue and cells. Beneath
the intestinal cells lies the lamina propria, a supportive connective tissue
rich in immune cells. The proximity of the microbiota to the lamina propria
and its multitude of immune cells and receptors provides opportunities for
bidirectional communication between the immune system and the microbes
throughout your life span.

The Small and Large Intestines

The small intestine is divided into three sections: The first segment, the
duodenum, is connected to the stomach; the middle section is called the
jejunum; and the third segment is called the ileum. It joins the large intestine
at an area called the cecum, and a sphincter known as the ileocecal valve
maintains a barrier between the small and large intestines to prevent backflow
of digestive contents and bacteria. It also controls the flow of digestive
contents into the large intestine in response to pressure from food reaching
the latter end of the ileum.

11
 2. Introducing the Gut Microbiome

12
 2. Introducing the Gut Microbiome

The internal structure of the small intestine is specialized to maximize its

surface area. This internal lining is bunched into finger-like projections called
villi, which are covered with tiny hair-like projections called microvilli. These
are coated with digestive enzymes. The extensive folding of the small intestine
increases its absorptive capacity by 600 times what it would be as a straight
tube, and it’s so adaptive that up to 50% of it can be lost or removed before its
functional capacity is affected.

Because it’s connected to the stomach, the duodenum is also fairly acidic
and high in oxygen. Here, bacterial numbers and diversity are only slightly
greater than what you would find in the stomach. However, numbers of
bacteria in the jejunum and ileum are two to four times greater than those in
the stomach or duodenum, and they’re also much more diverse. The cecum
is a large pouch where digested food can pool and provide a rich source of
nutrients for bacteria, making it a major site for bacterial growth.

Through the cecum, you pass into the large intestine, which plays an
important role in both fluid and electrolyte balance as it absorbs these
from feces. The large intestine is folded into three portions: the ascending,
transverse, and descending colon—the latter of which ends in an S-shaped
structure called the sigmoid colon. The sigmoid colon terminates at the
rectum, which controls the exit of feces via the external sphincter.

The large intestine forms stool by holding digestive contents in place while
absorbing water, electrolytes, and small amounts of vitamins and minerals.
Stool is usually about 75% water. The remaining 25% is composed primarily
of dead bacteria and indigestible fiber, along with some undigested fats,
minerals, and other dead cells. The large intestine contracts to move stool
toward the rectum, where defecation can take place.

The large intestine houses most of the gut microbiome. It’s filled with nearly
2 kilograms—or about 4 pounds—of microbes. There are approximately 10
times more bacteria in the large intestine than in the stomach and duodenum
and up to 2.5 times more than in the jejunum and ileum. The microbial
population here is so diverse because the environment is low in acid and
oxygen but rich in dietary fibers indigestible to humans. The large intestine
is also the primary site of bacterial fermentation, which is a process bacteria
use to convert that fiber to usable energy. Fermentation produces gases (such

13
 2. Introducing the Gut Microbiome

as methane), SCFAs (such as butyrate), and even some neurotransmitters.

Some bacteria also produce small amounts of vitamins such as biotin and
vitamin K.

The Second Brain

The gut has its own specialized nervous system, which has earned it the
title of the “second brain.” Our autonomic nervous system, which regulates
automatic processes like perspiration, still controls the digestive tract for the
most part, but the enteric nervous system of the gut can act independently.
Chemical messengers called neurotransmitters are produced by cells in the
digestive tract itself as well as nerves from the two branches of the autonomic
nervous system.

14
 2. Introducing the Gut Microbiome

The sympathetic branch controls your fight-or-flight response, while the

parasympathetic branch regulates digestion and helps you return to a calmer
state once you’ve escaped a threat. Most sympathetic signaling is sent along
splanchnic nerves in the abdomen.

The vagus nerve, which carries most of the parasympathetic signals, runs
straight from the brain to the gut. These signals control the wavelike
contractions that move food along, the secretion of digestive enzymes, and
the contraction and relaxation of sphincter muscles that control passage of
digestive contents throughout—and out of—the digestive tract.

What’s in Your Gut?

All three main domains of life can be found in the human gut: Eukarya
(which includes plants, animals, and fungi), Archaea, and Bacteria. As far
as researchers know, the human gut microbiome can be divided into 12
bacterial phyla. The phylum level of organization is general, like comparing
vertebrates to invertebrates. Ninety percent of the bacteria in the digestive
tract come from four groups: Bacteroidetes, Firmicutes, Actinobacteria, and
Proteobacteria. These large groups contain numerous genera, which you can
organize into more closely related groups of species.

A species of bacteria is defined by a high degree of structural and functional

similarity. However, it isn’t the same definition that is used to describe a
species of lizards or birds. At this point, species is the best word available, so it
is used to differentiate between members of a genus, just like you differentiate
between dogs and jackals. In some cases, species can be further divided into
strains. This is important to keep in mind because the activities and potential
health effects of bacteria are strain specific. Differentiating strains is similar to
differentiating between dogs and wolves. Within a single species, some strains
are sold as probiotic supplements, while others can cause GI diseases. As
researchers discover and categorize new organisms, the taxonomy changes.

The gut is remarkably diverse. In microbiome science, if the number of each

species in the gut is relatively proportional, the microbiome is more diverse.
If one species is disproportionately abundant in comparison to the others,
the microbiome is less diverse. However, not all researchers use both metrics,

15
 2. Introducing the Gut Microbiome

and it becomes more difficult to determine the diversity of a microbiome

with many species in disproportionate amounts or an even distribution of a
limited number of species. So, the meaning of diversity still varies from one
publication to the next.

Bacterial Exposure
Bacterial exposure in infancy has a significant and lasting effect on the gut
microbiome. Infants’ digestive tracts are primarily colonized during the birth
process. The bacterial colonies rapidly multiply and diversify for 2 to 3 years
before reaching the more stable adult composition. Delivery mode, gestation
time, and diet all play a role in shaping your gut microbiome.

A baby born vaginally after a full-term pregnancy will have a gut microbiome
similar to that of the mother within about 3 days. This is probably due to
exposure to colonic bacteria, such as Bifidobacteria, during birth. This is
likely why the dietary pattern of the mother significantly influences the
gut microbiome of her infant in the case of a vaginal birth. A baby born
via cesarean section, however, develops a less-diverse gut microbiome that
resembles the environment of the delivery room and the mother’s skin
microbiome. These differences appear to persist up to about 6 months of age,
and their impact on health and disease later in life is still unclear.

Breast milk delivers human milk oligosaccharides and bacteria, so babies

who breastfeed have more Bifidobacteria and lactobacilli in their microbiomes
compared to those who are formula-fed. The period of time before weaning
plays an important role in the development of immunotolerance to gut
microbes. Some evidence points to a connection between low microbial
diversity early in life and the development of eczema, asthma, and allergies later
in life, but the cause is still unknown. The infant microbiome becomes more
diverse once complex carbohydrates are introduced during or after weaning.

Finally, current theories suggest that early antibiotic use could lead to
lasting changes in the microbiome, such as reduced diversity and the growth
of antibiotic-resistant bacteria. The effects of short-term broad-spectrum
antibiotic use on the microbiome and metabolic function vary from person to
person, and they could last months or years.

16
 2. Introducing the Gut Microbiome

It’s estimated that about 60% of our bacterial inhabitants remain unchanged
throughout adulthood until old age, when the microbiome starts to lose
diversity. Researchers estimate that somewhere between 20% and 60% of
our bacterial diversity can be influenced by diet and exercise, with our genes
accounting for only 12%. It also appears that roughly one-third of the biome
is shared among humans, but there’s so much individual variability that no
two microbiomes are the same.

READING
Cossart, P. The New Microbiology. Washington DC: ASM Press, 2018.
https://www.perlego.com/book/1353534/the-new-microbiology-pdf.

Cullen, C. M., K. K. Aneja, S. Beyhan, C. E. Cho, S. Woloszynek, M. Convertino, S. J.

McCoy, et al. “Emerging Priorities for Microbiome Research.” Frontiers in Microbiology
11 (February 2020). https://doi.org/10.3389/fmicb.2020.00136.

Douglas, A. Fundamentals of Microbiome Science. Princeton, NJ: Princeton University

Press, 2021.

Flint, H. J. Why Gut Microbes Matter. Cham, Switzerland: Springer International

Publishing, 2020. https://doi.org/10.1007/978-3-030-43246-1.

Haller, D., ed. The Gut Microbiome in Health and Disease. Cham, Switzerland: Springer
International Publishing, 2018. https://doi.org/10.1007/978-3-319-90545-7.

17
How Researchers
Study the Gut
3
Microbiome

In 2011, a group of researchers made a “keystone

discovery” in gut microbiome research: People
could be organized into at least three groups called
enterotypes based on how their gut microbes were
distributed. However, new methods eventually
revealed flaws in the theory, and the three
proposed types of microbiomes might be less
distinct than initially thought. The seismic changes
around the idea of enterotypes reflect how gut
microbiome science is a way of becoming less
wrong over time. In this lecture, you’ll explore how
researchers study the gut microbiome as well as
a few questions you can ask to spot bad research.
You’ll also see the strengths and limitations of
common methods and how those methods are
evolving to give researchers a more accurate and
useful picture of human gut health.

18
 3. How Researchers Study the Gut Microbiome

The Gut Microbiome Research Process

Like any other scientific field, gut microbiome science begins and ends
with the scientific method. This is a process of making educated guesses, or
hypotheses, based on your observations and then testing the accuracy of your
guesses with experiments to collect more observations in a specific scenario.
The gold standard for hypothesis testing is a randomized, placebo-controlled
trial (RCT).

In an RCT, an intervention—like a specific probiotic—is compared to a

placebo, or an inert substance that shouldn’t have an effect. Ideally, the
experiment is also blinded, which means that neither the participants nor the
researchers know who’s getting what. This reduces the chances of bias or a
placebo effect. By comparing the intervention’s effects to the placebo’s effects,
researchers can be more certain that the intervention had some effect and that
the results weren’t due to chance.

Researchers are only able to get closer to correctly explaining a phenomenon

by ruling out other potential answers that are more likely to be wrong. In
some cases, they aren’t even trying to determine whether one thing causes
another. Instead, they might be looking for correlations, or relationships,
between two things. A study that looks for correlations is called an
observational study. Importantly, observational studies can help researchers
form hypotheses that can be tested with RCTs.

Many studies linking dietary patterns to the gut microbiome are performed
as observational studies. Researchers collect survey data and stool samples
from a large population and then compare something like their vegetable
intake to the diversity of their stool sample to draw a correlation. They may
go on to develop a hypothesis about certain vegetables supporting microbiome
diversity, which they could then test with an RCT. This is a key take-home
message: If someone says that a specific study proves something, they might
be more interested in making a persuasive statement than an accurate one. At
the moment, no causative relationships have been established between the gut
microbiome and any health or disease outcome.

19
 3. How Researchers Study the Gut Microbiome

The History of Microbiome Research

The field of microbiology emerged as a distinct science in the mid-1800s,
when Louis Pasteur used microscopy to demonstrate that microorganisms
were responsible for fermentation and food spoilage. At the time, the leading
hypothesis was that disease and fermentation happened spontaneously.
However, Pasteur’s new germ theory suggested that disease and spoilage were
caused by tiny organisms called germs. This was a huge step toward the most
accurate explanation researchers have so far, which is that microorganisms
cause both fermentation and disease.

In 1878, a German microbiologist named Robert

Koch developed four criteria for establishing
a cause-and-effect relationship between a
microbe and a disease: First, the microbe
should only be found in people with the
disease. Second, the microbe has to be
cultured, or grown, in a petri dish without
the presence of other organisms. Third, ROBERT
the microbe then needs to be introduced KOCH
to a healthy person or animal, and that
recipient needs to develop the disease in
question. Finally, the microbe needs to
be found in the recipient, without having
mutated in some way so as to make it a new
strain. Koch’s postulates have been modified
slightly to include microbial communities rather
than single microbes, but they still serve as criteria to
establish a causal relationship between gut microbes and health outcomes.

Today, when researchers collect a stool sample, they can preserve the genetic
material in that sample and then either amplify certain genes of interest to
identify specific microbes or look at all of the genetic material and try to piece
the profile of the microbiota together like a puzzle. In short, gene sequencing
allows researchers to see what microbes actually populate a sample. Such
techniques allow researchers to describe microbiomes in a few different ways.
They can calculate the alpha-diversity—or richness and evenness—of a single
sample based on the number and proportions of observable microbes, or

20
 3. How Researchers Study the Gut Microbiome

they can measure the microbial products, like SCFAs, in the sample. These
measurements give researchers an idea of what the microbes were doing when
the sample was collected.

These days, a fecal sample can also be transplanted from a donor host—
human or animal—into a recipient. When this is done for research purposes,
it’s considered an intervention. This would be an example of an RCT. The
recipient’s physiology or behavior can be studied to determine whether the
microbiota in the donor’s sample caused a change in the recipient. This
procedure is called a fecal microbiota transplantation (FMT), and it’s uniquely
capable of bringing researchers as close as possible to understanding a causal
relationship between microbes and disease.

Researchers now have many options for collecting, processing, and analyzing
microbiome samples. However, the more methods there are, the harder it is to
standardize procedures and replicate results between research groups. There
are also some known issues with common research methods. A sample can
be easily contaminated by the local environment, and sample storage and
processing can also affect the results. Moreover, microbes differ in their ability
to tolerate oxygen and withstand the processes used to extract their genetic
material, which means that certain species might be over- or underrepresented
based on the extraction methods. This makes it difficult to form consensus
statements about the gut microbiome and sometimes leads to premature
conclusions that later turn out to be incorrect.

Determining Fact versus Fiction

Dr. William Hanage, a Harvard University epidemiology professor,
recommends asking a few key questions as you read the latest microbiome
research while keeping the abovementioned limitations in mind.

First, did the researchers detect changes that actually matter? For example,
a 2021 study compared fermented foods to high-fiber foods and found that
people who ate the fermented foods had lower inflammatory markers than those
who ate the high-fiber foods. Some media outlets claimed that the fermented
foods were anti-inflammatory or that high-fiber foods cause inflammation.
However, the data really revealed that both groups had normal, healthy levels of

21
 3. How Researchers Study the Gut Microbiome

inflammatory markers before and after the study. So, compared to each other,
the participants might have had lower or higher inflammatory markers, but
they were never experiencing objectively high or low levels of inflammation. So,
did the change in inflammatory markers matter?

Second, did the study indicate causation or just correlation? Remember that
researchers haven’t established any cause-and-effect relationships between
the gut microbiome and any aspect of health and disease. And microbiomes
are so complex that they might never achieve a complete understanding of
cause and effect between the microbiome and human health. Establishing
causation is further complicated by the fact that researchers don’t know the
genomes of a great number of microbes, so they can’t identify all microbes in
a sample. This makes it difficult to suggest causal relationships between the
sample microbiome and health or disease. The ability to differentiate between
specific strains is also limited with certain techniques, meaning experiments
sometimes lack the resolution necessary to identify a strain of interest and link
it to any outcome.

Third, did the researchers identify an actual mechanism, and does it make
sense? A mechanism is a specific phenomenon that could explain an outcome,
like a metabolic process that a microbe uses to produce a SCFA. Many
researchers will use the idea of dysbiosis as the “mechanism” to explain the
results of their study. But in the words of Drs. Scott Olesen and Eric Alm,
biological engineering researchers out of the Massachusetts Institute of
Technology, dysbiosis is “a ‘mechanism-free’ cause of disease to which we can
retreat when plausible mechanistic explanations are discounted.”

Fourth, Hanage also encourages readers to question how well an experiment

reflects reality. For example, stool samples can be useful, but researchers
should be careful about the conclusions they draw from them. A human stool
sample closely represents the microbes that live in the lumen of the large

22
 3. How Researchers Study the Gut Microbiome

intestine. But that population is significantly different from the community

that you’d find in the mucosal layer of the large intestine or any part of the
small intestine. Despite this important distinction, many publications use the
term gut microbiome when they’ve actually only studied the stool microbiome.
So, when you consider whether an experiment reflects reality, you’re really
asking two questions: Are the terms precisely and accurately defined? And do
the results really apply to the human gut microbiome?

Finally, you should ask whether the results could be explained by anything
else. So many factors shape the gut microbiome—from geography to gender
and prescriptions to pets. Researchers call these confounding factors because
they distort the relationship between variables in a study. For example, when
the abundance of a microbe differs after an intervention, it’s tempting to
conclude that the difference is due to the intervention itself. But it could be
the result of something that’s almost impossible to account for, like whether
the participant had a childhood pet. The microbiota themselves can also
be confounding factors because they interact with one another in ways
researchers don’t understand—or haven’t discovered yet.

Genome Sequencing Advancement

Recent technological advancements in sample analysis have made genome
sequencing faster and more affordable. Whole genome sequencing, for
example, breaks the genome into small pieces, sequences each one, and then
puts them all together to get a complete genome sequence. It has only been
in use since 2006, but its accuracy allows researchers to update genomic
reference libraries as various labs discover new microbes. This is making the
view of the microbiome more complete and identification more reliable.

Gut scientists are also borrowing new statistical methods from other
sciences that are better suited to studying complex ecosystems. Mendelian
randomization, for example, is a method borrowed from epidemiology. It
looks at the differences in health outcomes between people who have a genetic
variation—or “mutation”—and those who don’t to discern whether a specific
risk factor is truly causing a certain health outcome. It has the ability to rule
out other potential causes because the genetic variation isn’t affected by any

23
 3. How Researchers Study the Gut Microbiome

confounding factors (such as age, sex, or lifestyle) that could be present in

traditional observational studies. Researchers can use this method to compare
the impact of a person’s genes against the impact of certain gut microbes to
estimate how causal the microbes might be.

The integration of these techniques, which analyze whole, complex systems

rather than singular microbes, has started to reshape how researchers think
about causation. Some are even questioning whether it’s appropriate to
apply the same set of criteria historically used to establish a cause-and-effect
relationship between a single microbe and a disease to an entire microbiome
and a disease. As a result, the relevance of Koch’s postulates has come under
fire. Perhaps one of the most important changes is that researchers are naming
these limitations and calling for more collaboration to standardize best
practices from sample collection to the reporting of results. Eventually, this
could lead to better translation from research to real life.

READING
Allaband, C., D. McDonald, Y. Vázquez-Baeza, J. J. Minich, A. Tripathi, D. A. Brenner,
R. Loomba, et al. “Microbiome 101: Studying, Analyzing, and Interpreting Gut
Microbiome Data for Clinicians.” Clinical Gastroenterology and Hepatology 17, no. 2
(2019): 218–230. https://doi.org/10.1016/j.cgh.2018.09.017.

Cani, P. D., E. Moens de Hase, and M. van Hul. “Gut Microbiota and Host Metabolism:
From Proof of Concept to Therapeutic Intervention.” Microorganisms 9, no. 6 (2021).
https://doi.org/10.3390/microorganisms9061302.

Cullen, C. M., K. K. Aneja, S. Beyhan, C. E. Cho, S. Woloszynek, M. Convertino, S. J.

McCoy, et al. “Emerging Priorities for Microbiome Research.” Frontiers in Microbiology
11 (February 2020). https://doi.org/10.3389/fmicb.2020.00136.

Hanage, W. “Microbiology: Microbiome Science Needs a Healthy Dose of Skepticism.”

Nature 512 (2014): 247–248. https://doi.org/10.1038/512247a.

Olesen, S. W., and E. J. Alm. “Dysbiosis Is Not an Answer.” Nature Microbiology 1 (2016):
1–2. https://doi.org/10.1038/nmicrobiol.2016.228.

Walter, J., A. M. Armet, B. B. Finlay, and F. Shanahan. “Establishing or Exaggerating

Causality for the Gut Microbiome: Lessons from Human Microbiota–Associated
Rodents.” Cell 180, no. 2 (2020): 221–232. https://doi.org/10.1016/j.cell.2019.12.025.

24
How to Spot Gut
Health Pseudoscience
4
The scientific method is a systematic approach
used by scientists to investigate and understand
natural phenomena. It involves several steps,
including formulating a hypothesis, designing
and conducting experiments, analyzing data,
and drawing conclusions based on the evidence
gathered. It relies on empirical evidence,
rigorous experimentation, and critical analysis.
Pseudoscience, however, refers to beliefs, theories,
or practices that are presented as scientific but
lack the characteristics of genuine scientific inquiry,
such as empirical evidence. Pseudoscientific
claims often lack consensus within the scientific
community and are frequently based on anecdotal
evidence or subjective experience. In this lecture,
you’ll examine several pseudoscientific gut health
claims and learn how to separate the science from
the science fiction.

25
 4. How to Spot Gut Health Pseudoscience

Identifying Pseudoscience
One of the most obvious indicators of pseudoscience is that it relies heavily on
anecdotal evidence, personal testimonials, appeals to authority, or subjective
experiences to support its claims. In addition, pseudoscientific claims tend to go
against the consensus of the scientific community. Consensus here means that
multiple rigorous investigations have consistently replicated the same results,
which gives researchers a degree of confidence that these results are reliable.
Pseudoscience also often lacks rigorous peer review and is not published in
reputable scientific journals. Peer review involves independent experts critically
evaluating and providing feedback on the research before it is published.

Pseudoscientific claims are often formulated in such a way that they cannot
be tested or disproven. Promoting unfalsifiable claims prevents scientific
progress, which relies on the ability to adapt and revise theories based on
new evidence. Peddlers of pseudoscience also tend to selectively choose data
that support their claims while disregarding or downplaying contradictory
evidence. In genuine scientific research, all relevant data are considered,
including both supporting and conflicting results. Finally, pseudoscientific
claims may be driven by financial motivations or conflicts of interest.

26
 4. How to Spot Gut Health Pseudoscience

“Leaky Gut”
One of the most common examples of pseudoscience is leaky gut. Essentially,
leaky gut refers to increased intestinal permeability, which means that
substances can pass between the cells of the intestinal wall more easily than
they normally would. The permeability of the intestinal lining does, in fact,
vary from person to person, and increased permeability is associated with
some health conditions. However, it’s important to note that leaky gut is not a
recognized medical condition that can be diagnosed or treated specifically.

Under normal conditions, the intestinal wall is semipermeable, allowing

certain substances to pass through in a controlled manner. However, certain
factors, such as GI disease, obesity, or a high-fat diet, may increase intestinal
permeability by affecting the proteins that hold the intestinal cells tightly
together. As these proteins loosen their hold, substances can pass between
the intestinal cells and encounter immune cells, which can trigger chronic
inflammation. Researchers can measure altered intestinal permeability in
humans, mostly by quantifying a specific protein or using a dual-sugar test.
However, there is currently no gold standard test. Also, altered intestinal
permeability is not, in itself, a disease, but it can be associated with certain
disease states, such as advanced intestinal disease.

Currently, tests for intestinal permeability are not diagnostic, and no causative
links have been established between altered intestinal permeability and
any disease. Additionally, there is no known treatment for this change in
permeability. It seems that preventing altered intestinal permeability is the
best course of action, and this may involve making healthy lifestyle choices.
A Westernized dietary pattern, a body mass index over 25, and intense
endurance exercise (especially under heat stress) are all associated with an
increased likelihood of this issue.

Unfortunately, some online “gut health gurus” claim to diagnose and treat
leaky gut based on vague symptoms, such as brain fog, fatigue, and GI
pain. However, there is no clear link between these symptoms and increased
intestinal permeability. So, in this case, a scientific reality is stretched into the
realm of pseudoscience.

27
 4. How to Spot Gut Health Pseudoscience

Selling Solutions
Another pattern is to create a problem to sell a solution. Many influencers
attract attention with fear-based marketing, like claiming that certain
substances, such as artificial sweeteners, will destroy the gut microbiome.
The Food and Drug Administration (FDA) has approved several artificial
sweeteners, including acesulfame K, aspartame, saccharin, and sucralose,
for use as sugar substitutes. Their impact on the gut microbiome is a newer
area of research. Some studies have exposed isolated cells to artificial
sweeteners, and the effects have ranged from increased hormone production
to inflammation. However, most rodent models and human data don’t show
any of these findings. So, based on the highest-quality data available, artificial
sweeteners are safe for both humans and their gut bacteria.

You may have also heard of comprehensive stool analysis tests that claim to
detect microbes in your gut that could be contributing to your illness or other
vague symptoms. These tests often come with recommendations for a specific
diet to fix any issues. However, there are several red flags associated with
these tests. For example, distributors establish their own reference ranges for
“normal” levels of organisms, despite the lack of a scientific consensus.

No current technology can identify all of the microbes present in the

fecal microbiome. Furthermore, no nutritional recommendations will
cause targeted changes to the microbiome. These stool tests also falsely
equate certain microbes with disease; however, some microbes are essential
inhabitants that likely play an important role in the development of
our immune systems. Without the ability to determine “ideal” relative
abundances of microbes or identify species at the strain level, these clinical
applications are limited. In conclusion, gut health protocols that claim to
diagnose dysbiosis or reset the gut are lacking in empirical evidence and
physiological probability.

What about tests that claim to identify food sensitivities? Unfortunately,

they’re not valid. To understand why, it’s helpful to know a little bit about
the immune system and the different types of antibodies. Antibodies are
produced in response to foreign substances entering the body, including
allergenic foods: Allergies are immune responses, so they’ll prompt the
production of antibodies. Immunoglobin E antibodies are involved in allergic

28
 4. How to Spot Gut Health Pseudoscience

responses, while immunoglobulin G (IgG) antibodies help the immune

system neutralize pathogens. An IgG antibody response is actually a sign of a
healthy immune system recognizing an antigen as familiar and harmless.

The idea behind food sensitivity testing is to look for certain antibodies that
supposedly appear when a specific food is presented. Food sensitivity tests
only measure one antibody, though: the IgG antibody. That is, these tests
will list foods that you’ve eaten in the past—foods that your immune system
recognizes as harmless—but removing those foods may lead to nutritional
deficiencies and psychological harm.

Detoxes and Cleanses

Cleanses and detoxes are marketed as a way to get rid of “toxins” in your
body, lose weight, and improve gut health. But the term toxins is used pretty
loosely in the detox diet industry. Pollutants, man-made chemicals, processed
food ingredients, and heavy metals are often grouped together under this
umbrella term, which is poorly defined to begin with. The truth is, there’s no
evidence that any commercial detox diet will remove any of these substances
from your body. Despite this, many practitioners still prescribe and publish
“clinical detox” procedures, which is concerning.

Your body already has ways to remove waste products from your system
through enzymatic pathways and excretory systems in the liver, kidneys, GI
tract, skin, and lungs. The best way to support your body’s detoxification
system is to eat a healthy diet that’s high in fruits, vegetables,
whole grains, beans, poultry, and fish. The
risks of detox diets and cleanses are serious,
including nutrient deficiencies, electrolyte
imbalances, diarrhea, dehydration,
disordered eating, and even
death. Some diets involve long-
term fasting, exclusion of solid
foods, laxative use, unregulated
supplements, extended sauna use,
and strict dietary rules.

29
 4. How to Spot Gut Health Pseudoscience

You may have also heard that you should protect your gut from yeasts. Yeasts
are eukaryotic microorganisms classified as fungi. They can be found in both
the oral and vaginal cavities, and they can also be detected in adult stool
samples. The most abundant group of yeasts found in the human body is
Candida, followed by Saccharomyces and Malassezia. Though they make up a
small portion of the gut microbiome, emerging research suggests that they’re
essential members of the community. They’ve even earned their own title: the
mycobiome.

CANDIDA AURIS

Some yeasts can cause infections, particularly Candida, but the evidence does
not support claims that Candida causes GI distress or impaired gut barrier
function or that it leads to nebulous symptoms, such as fatigue. However,
Candida can delay the healing time of ulcers in IBD and may overpopulate
the GI tracts of newborns, making them susceptible to a systemic infection.
To diagnose intestinal Candida infection, endoscopy and histology are
required, while systemic fungemia requires a blood test.

Studies suggest that a large proportion of the yeasts found in stool samples
actually come from our diet or saliva. So, making dietary modifications to
avoid yeast-containing food and brushing and flossing frequently can help
reduce the amount of certain yeasts in stool, but that may not reflect what’s
actually going on in your gut. Nevertheless, unsupported hysteria around
Candida has given rise to plenty of pseudoscientific claims that advocate for
ineffective dietary changes.

30
 4. How to Spot Gut Health Pseudoscience

Contrary to popular belief, eating refined carbohydrates is not associated

with elevated Candida albicans in humans. Also, adding sugar to the diet only
raises fecal Candida albicans in individuals who already had high levels of oral
yeast. Moreover, fecal counts don’t indicate actual intestinal colonization, and
oral yeasts are likely ingested with saliva without colonizing the intestines of
healthy individuals. It’s also important to know that there are no interventions
to cleanse the gut of yeasts, and even antifungal drugs can’t eliminate them
entirely. However, antifungal drugs are effective treatments when fungal
infections are present.

Supplements
Lately, many fitness personalities have been talking about taking collagen
supplements to improve gut health. Collagen is a protein that’s important
for the structure of our bodies, but there’s no evidence yet that it affects gut
function or the gut microbiome. It is broken down in our bodies just like
other proteins, so it’s unlikely to have a direct effect on the lamina propria in
the gut, which is one of the proposed mechanisms by which some suggest it
could “heal” the gut.

You might also encounter enzyme supplements that supposedly aid in

digestion. To evaluate how well digestive enzymes work, you need to
understand the differences in pH along our digestive tract. The pH levels
in our saliva, stomach, small intestine, and large intestine are all different.
Enzymes are active at specific pH ranges, and if they’re outside of that
range for too long, they’ll lose their shape and function, a process called
denaturation. Our bodies produce different types of enzymes to break down
the macronutrients we consume, like carbohydrates, proteins, and fats. If
we lack certain enzymes, as in the case of lactose intolerance, we might
experience digestive issues like gas, bloating, or diarrhea.

Enzyme supplements claim to alleviate these issues, but there isn’t much
evidence to support their effectiveness across the board. Some manufacturers
try to protect the enzymes from denaturation by encapsulating them in a
coating, but even prescription-strength enzymes can struggle to survive the

31
 4. How to Spot Gut Health Pseudoscience

acidic environment of the stomach. In fact, well-designed RCTs have shown

that only about half the participants notice any improvements after using
digestive enzymes.

And while powdered produce blends are often marketed as a way to improve
digestion and cardiovascular health, as well as providing the equivalent of
multiple servings of fruits and vegetables, the evidence here is also pretty
mixed. Most of the research has been done on specific brands of these
powders, and the studies have often been carried out by physicians who are
also selling the products—which makes the results suspect, to say the least.
Some studies have shown that they can reduce markers of protein, lipid,
and DNA oxidation or damage to these molecules. But the evidence is still
limited, and these products are sold as supplements, not as food. This means
that their blends are often proprietary, and testing for purity and efficacy
isn’t required. Plus, some vitamin and herbal supplements can interact with
prescription medications.

READING
Chen, Chung-Yu, Cheng-Hao Tien, Yue-Hwa Chen, D. Garrido, A. Farzi, H. Herzog,
Hsien-Yu Fan, and Yang-Ching Chen. “Effect of Sucralose Intake on Human and
Mouse/Rat Gut Microbiota Composition: A Systematic Review and Meta-Analysis.”
Food Reviews International (2023). https://doi.org/10.1080/87559129.2023.2212045.

Flores R., J. Shi, B. Fuhrman, X. Xu, T. D. Veenstra, M. H. Gail, P. Gajer, et al. “Fecal
Microbial Determinants of Fecal and Systemic Estrogens and Estrogen Metabolites:
A Cross-Sectional Study.” Journal of Translational Medicine 10, no. 1 (2012): 1–11.
https://doi.org/10.1186/1479-5876-10-253.

Gingras, B. A., and J. A. Maggiore. “Performance of a New Molecular Assay for the
Detection of Gastrointestinal Pathogens.” Access Microbiology 2, no. 10 (2020).
https://doi.org/10.1099/acmi.0.000160.

Lacour, M., T. Zunder, R. Huber, A. Sander, F. Daschner, and U. Frank. “The

Pathogenetic Significance of Intestinal Candida Colonization: A Systematic Review
from an Interdisciplinary and Environmental Medical Point of View.” International
Journal of Hygiene and Environmental Health 205, no. 4 (2002): 257–268.
https://doi.org/10.1078/1438-4639-00159.

Leech, B., E. McIntyre, A. Steel, and D. Sibbritt. “Risk Factors Associated with Intestinal
Permeability in an Adult Population: A Systematic Review.” International Journal of
Clinical Practice 73, no. 10 (2019): e13385. https://doi.org/10.1111/ijcp.13385.

32
 4. How to Spot Gut Health Pseudoscience

McFarland, L. V., C. T. Evans, and E. J. C. Goldstein. “Strain-Specificity and Disease-

Specificity of Probiotic Efficacy: A Systematic Review and Meta-Analysis.” Frontiers in
Medicine 5 (2018): 124. https://doi.org/10.3389/fmed.2018.00124.

Ramezani Ahmadi, A., E. Rayyani, M. Bahreini, and A. Mansoori. “The Effect of

Glutamine Supplementation on Athletic Performance, Body Composition, and Immune
Function: A Systematic Review and a Meta-Analysis of Clinical Trials.” Clinical
Nutrition 38, no. 3 (2019): 1076–1091. https://doi.org/10.1016/j.clnu.2018.05.001.

Stapel, S. O., R. Asero, B. K. Ballmer-Weber, E. F. Knol, S. Strobel, S. Vieths, and

J. Kleine-Tebbe. “Testing for IgG4 against Foods Is Not Recommended as a
Diagnostic Tool: EAACI Task Force Report.” Allergy 63, no. 7 (2008): 793–796.
https://doi.org/10.1111/j.1398-9995.2008.01705.x.

Tepler, A., G. Hoffman, S. Jindal, N. Narula, and S. C. Shah. “Intake of Artificial

Sweeteners among Adults Is Associated with Reduced Odds of Gastrointestinal Luminal
Cancers: A Meta-Analysis of Cohort and Case-Control Studies. Nutrition Research 93
(2021): 87–98. https://doi.org/10.1016/j.nutres.2021.07.007.

Tomicić, S., G. Norrman, K. Fälth-Magnusson, M. C. Jenmalm, I. Devenney, and M. F.

Böttcher. “High Levels of IgG4 Antibodies to Foods during Infancy Are Associated with
Tolerance to Corresponding Foods Later in Life.” Pediatric Allergy and Immunology 20,
no. 1 (2009): 35–41. https://doi.org/10.1111/j.1399-3038.2008.00738.x.

33
The Microbiome
and Gastrointestinal
5
Disease

In 1984, Dr. Barry Marshall drank a microbial

cocktail to intentionally infect himself with
Helicobacter pylori. After years of failed attempts in
animal studies, he hoped to fulfill Koch’s postulates
and prove that H. pylori was the cause of peptic
ulcers. He didn’t develop any peptic ulcers, but he
did experience nausea, bad breath, and gastritis.
This allowed him to establish a causal relationship
between H. pylori and gastritis but not with peptic
ulcers. However, Dr. Marshall and his collaborator
Dr. J. Robin Warren were still later awarded the
Nobel Prize for Physiology or Medicine for their
discovery that H. pylori could colonize the stomach
and its relationship with gastritis and peptic ulcers.
Dr. Marshall’s experiment demonstrates how
complicated the relationship can be between the
microbiome and GI disease—which is what you will
learn about in this lecture.

34
 5. The Microbiome and Gastrointestinal Disease

The Difficulty of Determining

Pathogenicity
Your microbiome is under constant surveillance by your intestinal cells,
which have the difficult task of defending against pathogens while remaining
tolerant of the other microbes. Some of the native, or commensal, microbes
can slip past these defenses, only to become pathogenic under specific
circumstances. Whether a microbe becomes pathogenic is likely determined
by the host’s genetics, intestinal immune activity, and the overall composition
of their gut microbiome. In other words, one beneficial microbe for you
could be a pathogen for someone else. It’s challenging to make sense of the
relationship between microbes and disease because, in many cases, studies can
only identify microbes down to the genus or species level—and determining
pathogenicity requires analysis at the subspecies or strain level.

However, several studies have identified differences in the gut microbiota

of people with a disease versus healthy individuals, and some interesting
patterns have emerged. Many diseases are associated with lower levels of both
taxonomic and functional diversity. That is, people with certain diseases
often present with fewer distinct species of microbes, and there’s less genetic
variation among the species that do populate their gut. This lower level of
diversity is often due to a lack of species richness compared to what’s seen in
healthy individuals. In some diseases, a sparser number of microbial species
coincides with higher levels of potential pathogens or lower levels of beneficial
microbes.

IBS is often characterized this way, with lower microbial diversity in the
intestine. But IBS is also often associated with a higher level of intestinal
permeability. That means the mucosal lining of the intestine is more likely to
let molecules (which could be pathogens) cross the intestinal barrier. Increased
intestinal permeability could allow microbe-associated inflammatory
substances to enter circulation and trigger a mild but chronic inflammatory
response. Some IBS symptoms, like abdominal pain, are linked to alterations
of the gut-brain axis: a bidirectional communication system between the gut
microbiome and the central nervous system, which regulates the activity of
the GI tract. So, it wouldn’t be accurate to say that lower microbial diversity
causes IBS.

35
 5. The Microbiome and Gastrointestinal Disease

Researchers are faced with similar uncertainties in the case of small intestinal
bacterial overgrowth (SIBO), which is a condition characterized by an
abnormally high concentration of bacteria in the small intestine, especially
the types that should be found in the large intestine. Symptoms often include
bloating and gas, and in diagnostic tests, people with SIBO will exhale
different levels and ratios of gasses compared to healthy people. These gasses
are only produced by bacteria, which is how they can be used to estimate a
potential overgrowth of bacteria in the small intestine.

However, research on SIBO suggests that the presence of the microbes may
not play as large of a role in these symptoms as the activity of the microbes
does. In other words, you might have a higher-than-average number of
microbes in your small intestine, but that doesn’t necessarily mean you’ll
have symptoms of SIBO. This microbial overabundance could be caused by
several factors. So, once again, you’re left to question the utility of analyzing
the taxonomic diversity without evaluating changes in the function of the
microbiome.

Fecal Microbiota Transplantation

IBS and SIBO both teach the same lesson: It can’t be said for certain that
lower microbial diversity or the abundance of certain microbes are a potential
cause or consequence of GI disease activity. But if you want to find out, some
study designs could provide clarity. For example, discordant twin studies use
identical twins with different health statuses to discern the role of genetics
versus other factors in causing disease. Identical twins share more genes than
any other relatives share with one another; if one twin has a genetic disease,
the other will likely have it as well. This allows researchers to attribute
differences in their health to other factors, like their microbiota or the
environment.

Unfortunately, these twin studies have some shortcomings. For example, it’s
not possible to control for some variables, like long-term dietary intake and
exposure to environmental factors. To do so, researchers have used FMT to
closely mimic a variety of different diseases in rodent models. Rodents who

36
 5. The Microbiome and Gastrointestinal Disease

receive an FMT from people with IBD will develop IBD-like symptoms,
which points to the possible role of the microbiome in initiating the disease
process.

Studies like these have led to a few theories about the role of the microbiome
in GI diseases like IBD or IBS. Both IBD and IBS are associated with lower
gut microbiome diversity compared to people without a GI disease. In both
cases, the ratios of beneficial to potentially pathogenic microbes are skewed.
For example, compared to healthy controls, fecal samples from people with
IBD will often reveal a lower abundance of anti-inflammatory species, such
as Faecalibacterium prausnitzii, and higher levels of pro-inflammatory species
of Enterobacteriaceae. This skewed ratio suggests that the elevated immune
activity could actually be a response to unusually high levels of opportunistic
pathogens.

FMT can also be used as an effective treatment for certain GI diseases, with
the most prolific effects in treatment-resistant Clostridium difficile infections
C. difficile is a commensal microbe, so it usually exists in harmony with
other members of the microbiome. But certain conditions—like long-term
antibiotic use—can disrupt the microbiome, allowing C. difficile to overcome
the competition and start producing toxins that cause severe diarrhea. When
strong antibiotics aren’t enough to resolve a C. difficile infection, FMT
from a healthy donor is incredibly effective. FMT has also shown promise
for reducing the symptoms of IBS, and in both cases, the improvements
in symptoms are associated with lasting changes to the recipient’s gut
microbiome.

These findings suggest that at least some symptoms of certain diseases are
much more likely a consequence, rather than a cause, of gut microbiome
characteristics. However, it’s still unclear which microbes could be playing
the greatest role. Other research indicates that while the microbiome might
not directly cause any disease, there are some microbes that could predict or
even raise someone’s risk of developing a GI disease later in life. For example,
high levels of Fusobacterium nucleatum have been observed with remarkable
consistency in patients with colorectal cancer, and intervention studies have
found that this microbe can promote tumor growth.

37
 5. The Microbiome and Gastrointestinal Disease

Dietary Management
When it comes to diseases with complex, poorly understood causes—like IBD
or IBS—there are no clear means for prevention. But it is possible to reduce
your risk of developing colorectal cancer or an infectious disease, and there
are several ways to alleviate symptoms of incurable diseases. Research suggests
that a prudent dietary pattern could reduce your risk of colorectal cancer by
about 20%. One model diet is the Dietary Approaches to Stop Hypertension
(DASH) diet. The DASH diet emphasizes fruits, vegetables, whole grains,
poultry, low-fat dairy, beans, and nuts and recommends limiting saturated
fats and processed foods that are often high in sodium.

If you’re managing a chronic GI disease like IBS or IBD, you’ll likely come
across a lot of conflicting information about the foods you should exclude
from your diet. Some situations do warrant the exclusion of specific foods, but
generally, it’s best to follow a prudent, plant-centric, inclusive dietary pattern
that provides as many diverse foods as possible. That will be more nutritious
for you, and it will also provide a wider variety of nutrient sources to your gut
microbes.

That being said, there are some evidence-based diets that can help to manage
GI diseases and their symptoms. The most obvious example would be a
gluten-free diet for people with celiac disease. Celiac disease is an autoimmune
condition that causes severe damage to the intestines in response to the wheat
protein gluten. People with non-celiac gluten sensitivity might feel better when

38
 5. The Microbiome and Gastrointestinal Disease

they eliminate gluten, but this could actually be due to the coincidental removal
of fructans, which are fermentable carbohydrates found in wheat products.
That leads into the next reasonable elimination diet: the low-FODMAP diet.

FODMAP stands for fermentable oligosaccharides, disaccharides,

monosaccharides, and polyols. FODMAPs are highly fermentable
carbohydrates found in a number of different grains, fruits, and vegetables.
The fructans in wheat products are one example. Microbes can potentially
produce a lot of gas when they ferment these carbohydrates to produce
energy, and some of these FODMAPs also pull a lot of water into the
intestines. This can result in bloating, abdominal pain, and loose stool.
People with IBS might experience more severe symptoms because of the
altered physiology of their intestines. A low-FODMAP diet only limits
FODMAPs for a short period of time before systematically reintroducing
them to test a person’s tolerance to each one.

There are many other restrictive dietary patterns that are only supported by
anecdotes. The specific carbohydrate diet, for example, was developed in
the 1920s as a treatment for celiac disease before medical professionals knew
gluten was the culprit; they thought dietary carbohydrates were to blame for
people’s symptoms. In the 1990s, a biochemist repopularized the specific
carbohydrate diet after her child was diagnosed with celiac disease, but she
modified it to create specific phases during which you could only eat certain
foods. Unfortunately, she made a number of erroneous claims about the diet
as a treatment for other conditions, including autism spectrum disorder, none
of which are supported by any evidence.

The specific carbohydrate diet has been studied to some extent—in Crohn’s
disease rather than celiac disease—but so far, the research has shown that
it doesn’t perform any better than other prudent, whole-food-based dietary
patterns. It could also increase the risk of nutrient deficiencies in populations
who are already at increased risk because their disease has damaged their
intestinal lining.

READING
Avuthu, N., and C. Guda. “Meta-Analysis of Altered Gut Microbiota Reveals Microbial and
Metabolic Biomarkers for Colorectal Cancer.” Microbiology Spectrum 10, no. 4 (2022).
https://doi.org/10.1128/spectrum.00013-22.

39
 5. The Microbiome and Gastrointestinal Disease

Biesiekierski, J. R., S. L. Peters, E. D. Newnham, O. Rosella, J. G. Muir, and P.

R. Gibson. “No Effects of Gluten in Patients with Self-Reported Non-celiac
Gluten Sensitivity after Dietary Reduction of Fermentable, Poorly Absorbed,
Short-Chain Carbohydrates.” Gastroenterology 145, no. 2 (2013): 320–328.
https://doi.org/10.1053/j.gastro.2013.04.051.

Elli, L., C. Tomba, F. Branchi, L. Roncoroni, V. Lombardo, M. T. Bardella, F. Ferretti,

et al. “Evidence for the Presence of Non-celiac Gluten Sensitivity in Patients with
Functional Gastrointestinal Symptoms: Results from a Multicenter Randomized
Double-Blind Placebo-Controlled Gluten Challenge.” Nutrients 8, no. 2 (2016): 84.
https://doi.org/10.3390/nu8020084.

Illescas, O., M. Rodríguez-Sosa, and M. Gariboldi. “Mediterranean Diet to Prevent the

Development of Colon Diseases: A Meta-Analysis of Gut Microbiota Studies.” Nutrients
13, no. 7 (2021): 2234. https://doi.org/10.3390/nu13072234.

Limketkai, B. N., Z. Iheozor-Ejiofor, T. Gjuladin-Hellon, A. Parian, L. E. Matarese,

K. Bracewell, J. K. MacDonald, et al. “Dietary Interventions for Induction and
Maintenance of Remission in Inflammatory Bowel Disease.” Cochrane Database of
Systematic Reviews 2 (2019). https://doi.org/10.1002/14651858.CD012839.pub2.

McFarland, L. V., and S. Goh. “Are Probiotics and Prebiotics Effective in the Prevention
of Travellers’ Diarrhea: A Systematic Review and Meta-Analysis.” Travel Medicine and
Infectious Disease 27 (2019): 11–19. https://doi.org/10.1016/j.tmaid.2018.09.007.

Parra-Soto, S., D. Ahumada, F. Petermann-Rocha, J. Boonpoor, J. L. Gallegos, J. Anderson,

L. Sharp, et al. “Association of Meat, Vegetarian, Pescatarian and Fish-Poultry
Diets with Risk of 19 Cancer Sites and All Cancer: Findings from the UK Biobank
Prospective Cohort Study and Meta-Analysis.” BMC Medicine 20, no. 1 (2022): 79.
https://doi.org/10.1186/s12916-022-02257-9.

Saffouri, G. B., R. R. Shields-Cutler, J. Chen, Y. Yang, H. R. Lekatz, V. L. Hale, J. M.

Cho, et al. “Small Intestinal Microbial Dysbiosis Underlies Symptoms Associated
with Functional Gastrointestinal Disorders.” Nature Communications 10 (2019): 1–11.
https://doi.org/10.1038/s41467-019-09964-7.

van Lanen, A.-S., A. de Bree, and A. Greyling. “Efficacy of a Low-FODMAP Diet in Adult
Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis.” European Journal of
Nutrition 60 (2021): 3505–3522. https://doi.org/10.1007/s00394-020-02473-0.

Vonaesch, P., M. Anderson, and P. J. Sansonetti. “Pathogens, Microbiome and the Host:
Emergence of the Ecological Koch’s Postulates.” FEMS Microbiology Reviews 42, no. 3
(2018): 273–292. https://doi.org/10.1093/femsre/fuy003.

40
The Microbiome
and Immunity
6
During the 1918 influenza pandemic, enemas were
given to patients suffering from severe pneumonia
as a way to help them rehydrate and potentially
remove toxins and waste from the body. At the
time, the use of enemas was a common medical
practice and was thought to have therapeutic
benefits. It turns out that enemas did not, in fact,
combat influenza. But even wrong turns in science
can sometimes lead to productive outcomes. Of
the many enemas doctors administered to patients
with influenza, some contained fecal matter from
healthy individuals—and this led to a surprising
discovery: Patients who received such enemas
recovered more quickly from pneumonia than
those not receiving the treatment. This observation
eventually led to the theory that there might be a
connection between the gut microbiome and the
immune system. In this lecture, you’ll explore that
connection.

41
 6. The Microbiome and Immunity

Innate and Adaptive Immunity

Immunity refers to an organism’s ability to resist infection and disease by
recognizing and eliminating foreign substances, such as viruses, bacteria, and
other pathogens. The GI immune system, also known as the gut-associated
lymphoid tissue, is the defense system of your gut. It’s a complex network of
immune cells and tissues that play a critical role in maintaining the health
and function of the GI tract.

The GI immune system consists of several specialized structures, including

Peyer’s patches, mesenteric lymph nodes, and isolated lymphoid follicles,
which are scattered throughout the intestinal mucosa. These structures
contain a variety of immune cells that work together to detect and respond
to pathogens and other foreign substances, initiating immune responses to
clear the threat. The GI immune system is able to protect against the invasion
of pathogens and harmful substances while also maintaining tolerance
to harmless food and commensal bacteria. It does this by employing two
different but synergistic arms: the innate immune system and the adaptive
immune system. While both systems work together to maintain gut
homeostasis and protect against pathogens, they differ in how they respond to
an infection.

The innate immune system is your first line of defense. You were born with
it. It provides rapid, nonspecific defense against all invading pathogens alike.
It uses physical and chemical barriers, like your skin and stomach acid, as
well as specialized immune cells, like macrophages, dendritic cells, and innate
lymphoid cells. These cells have pattern-recognition receptors that allow
them to recognize conserved molecular patterns on the surface of pathogens.
When immune cells “recognize” these patterns, they trigger an immediate
response to eliminate the pathogen. Innate immune cells also secrete chemical
messengers called cytokines and chemokines that recruit other immune cells
to the site of infection and activate adaptive immune responses.

The adaptive immune system provides specific, long-lasting defense against

a particular pathogen. The adaptive immune response starts with antigen-
presenting cells, such as dendritic cells and macrophages. These cells identify
potential pathogens as foreign, recognizing specific substances, called

42
 6. The Microbiome and Immunity

antigens, on their surfaces. Once they’ve identified a foreign pathogen, they

literally catch and digest it. The antigen-presenting cells then go around
showing the antigen’s structure to T cells, which are white blood cells that
recognize the antigen and kick-start the immune response if necessary. The
T cells can then activate B cells, another type of white blood cell. B cells
produce antibodies, which are specialized proteins that can bind to the
antigens and neutralize the pathogen.

After the infection is cleared, a special, long-lived type of B cell called a

memory B cell remains. These B cells allow the adaptive immune system
to generate immunological memory, which helps the body respond more
quickly and effectively to subsequent infections by the same pathogen while
maintaining immune tolerance to the body’s own cells. If the body is exposed
to the same pathogen again, memory B cells will produce large quantities of
antibodies specific to the antigens of the previously encountered pathogen.
This allows the immune system to quickly and efficiently neutralize the
pathogen before it can cause significant harm.

43
 6. The Microbiome and Immunity

Importantly, these antibodies are also used to identify the body’s own cells
and harmless antigens to prevent an over-reactive immune response. Of
course, this system can malfunction. Allergies are one common example,
when the immune system misidentifies harmless foreign substances in the
environment as harmful and attacks them. Similarly, autoimmune diseases
occur when the immune system attacks the body’s own healthy cells.

The Gut Immune System

The gut immune system is intimately connected to the rest of the body’s
immune system through a complex network of cells, cytokines, and signaling
pathways. The gut is a major site of interaction between the host and the
environment, with the gut microbiota and dietary antigens constantly
stimulating the immune system. As a result, the gut immune system has a
significant impact on the development and function of the entire immune
system, and dysregulation of gut immune responses can have far-reaching
consequences.
The gut immune system is constantly communicating with the rest of the
body, and one of the key pathways is through the lymphatic system. This
system produces and stores white blood cells. The lymphatic vessels in the gut
drain into the mesenteric lymph nodes. These lymph nodes serve as a hub for
immune activation and cell trafficking, which is the regulated movement of
cells to different areas of the body via the bloodstream or lymphatic system.
From the mesenteric lymph nodes, immune cells can travel to other lymphoid
organs, such as the spleen and thymus, where they can influence immune
responses throughout the body.

The gut immune system also communicates with the rest of the body’s
immune system through the production of cytokines and other signaling
molecules. These send signals that directly affect what other cells do.
However, dysregulation of these communication systems can lead to immune-
mediated diseases, such as IBD, in which the dysregulation of innate immune
responses can lead to chronic inflammation and tissue damage.

44
 6. The Microbiome and Immunity

Human studies have shed some light on how the early gut microbiome—
during the first few years of life—shapes the immune system. For example,
research has shown that the gut microbiome is essential for the maturation
of immune cells, particularly T cells, which are crucial for adaptive immune
responses. In a study of infants, the presence of specific bacterial species in
the gut was associated with an increase in the number of T cells and their
maturation markers, suggesting a role for the gut microbiome in T cell
maturation.

The gut microbiome also plays a role in regulating innate immune responses.
Studies have shown that specific bacterial strains can activate innate immune
cells, such as dendritic cells, macrophages, and natural killer cells, promoting
immune activation and inflammation. This early exposure to microbial
stimuli helps to shape the innate immune response and provides protection
against later infections.

45
 6. The Microbiome and Immunity

In a mature immune system, regulatory T cells (or Tregs) play a critical role
in immune tolerance, preventing harmful immune responses to harmless
antigens. Studies have shown that the gut microbiome is essential for the
development and maturation of Tregs and that specific bacterial strains can
induce the generation of Tregs. This early exposure to microbial stimuli helps
the immune system learn to distinguish between pathogenic antigens—like
a bacterial infection—and beneficial microbes. Early microbial exposure also
helps the immune system learn to recognize and tolerate the body’s own cells.

The gut microbiome also influences the production of antibodies, which play
a crucial role in adaptive immune responses. Studies have shown that infants
with a diverse gut microbiome have higher levels of antibody-producing
B cells, suggesting that the gut microbiome supports the development of
adaptive immune responses. Microbes can also help regulate the immune
system with SCFAs. These are produced when gut bacteria ferment dietary
fiber; they have immune-modulating properties and can regulate the balance
between pro- and anti-inflammatory responses.

However, the relationship between the microbiome and the immune system
isn’t always perfectly functional or even positive. In molecular mimicry,
microbial antigens that are similar to human antigens can sometimes trigger
an autoimmune response. For example, consider multiple sclerosis, a disease
in which the immune system attacks the nervous system. There is evidence
that gut bacteria can produce antigens that resemble myelin, a component of
nerve fibers. These microbial antigens can then trigger immune responses that
cross-react with myelin, leading to autoimmune damage.

Immune System “Boosting”

Can you “boost” your immune system by way of your gut microbes? Some
influencers recommend letting your children play in the dirt, washing your
hands less, or taking certain supplements. Many of these recommendations
are based on the “old friends” hypothesis, which suggests that modern
lifestyles have sheltered us from exposure to certain microorganisms that
were once present in our natural environment. These microbes—the “old
friends”—include types of commensal bacteria as well as helminths, a kind

46
 6. The Microbiome and Immunity

of parasitic worm. Supposedly, immune deficiencies arise and become

widespread when we’re not exposed to these microorganisms throughout
our lives.

Most of the evidence comes from epidemiological studies of people who live
in rural or farming communities, where it’s more common to be exposed to
a wide range of microorganisms. These people tend to have a lower incidence
of allergies, asthma, and autoimmune diseases compared to those who live in
urban areas. In addition, animal studies have shown that exposure to some
types of microorganisms, such as helminths and certain bacteria, can reduce
inflammation and improve immune function. Clinical trials have introduced
helminths into patients with autoimmune disorders, such as multiple sclerosis
and IBD—and these little parasites might have helped. Symptoms sometimes
did improve.

However, not all of the available evidence supports the “old friends”
hypothesis. There is an association between rural living and lower incidence
of chronic inflammatory diseases, but it may be confounded by other
factors, such as diet and lifestyle. Exposure to certain microorganisms may
increase the risk of infectious diseases and other health problems. And
while some animal and clinical studies have shown that exposure to certain
microorganisms can improve immune function, the specific mechanisms are
still unclear.

Plenty of products claim to have immune-boosting properties, but boosting

the immune system is a myth. First of all, what is meant by “boosting” the
immune system? Are you just amplifying the body’s immune response? If so,
be careful. A hyperactive immune system can lead to autoimmune diseases,
allergies, and chronic inflammation. Instead of focusing on “boosting” the
immune system, it is more important to maintain a healthy lifestyle, including
a balanced diet, regular exercise, adequate sleep, and stress reduction.

Diet is one of the most important lifestyle factors that can influence the gut
microbiome and the immune system. A diet high in fiber and plant-based
foods can promote the growth of beneficial bacteria in the gut. In turn, the
beneficial bacteria can fend off pathogens and help regulate your normal
immune function by interacting with your immune cells. Bacteria also create
immune-regulating SCFAs as a byproduct when they ferment fiber.

47
 6. The Microbiome and Immunity

READING
Belkaid, Y., and T. W. Hand. “Role of the Microbiota in Immunity and Inflammation.” Cell
157, no. 1 (2014): 121–141. https://doi.org/10.1016/j.cell.2014.03.011.

Berer, K., and G. Krishnamoorthy. “Microbial View of Central Nervous

System Autoimmunity.” FEBS Letters 588, no. 22 (2014): 4207–4213.
https://doi.org/10.1016/j.febslet.2014.04.007.

Borody, T. J., E. F. Warren, S. Leis, R. Surace, O. Ashman, and S. Siarakas. “Bacteriotherapy

Using Fecal Flora: Toying with Human Motions.” Journal of Clinical Gastroenterology
38, no. 6 (2004): 475–483. https://doi.org/10.1097/01.mcg.0000128988.13808.dc.

Frank, D. N., A. L. St. Amand, R. A. Feldman, E. C. Boedeker, N. Harpaz, and N. R. Pace.

“Molecular-Phylogenetic Characterization of Microbial Community Imbalances in
Human Inflammatory Bowel Diseases.” Proceedings of the National Academy of Sciences
104, no. 34 (2007): 13780–13785. https://doi.org/10.1073/pnas.0706625104.

Gensollen, T., and R. S. Blumberg. “Correlation between Early-Life Regulation of the

Immune System by Microbiota and Allergy Development.” Journal of Allergy and Clinical
Immunology 139, no. 4 (2017): 1084–1091. https://doi.org/10.1016/j.jaci.2017.02.011.

Mowat, A. M., and W. W. Agace. “Regional Specialization within the Intestinal

Immune System.” Nature Reviews Immunology 14, no. 10 (2014): 667–685.
https://doi.org/10.1038/nri3738.

Neurath, M. F. “Targeting Immune Cell Circuits and Trafficking in

Inflammatory Bowel Disease.” Nature Immunology 20, no. 8 (2019): 970–979.
https://doi.org/10.1038/s41590-019-0415-0.

Rook, G. A. “Regulation of the Immune System by Biodiversity from the Natural

Environment: An Ecosystem Service Essential to Health.” Proceedings
of the National Academy of Sciences 110, no. 46 (2013): 18360–18367.
https://doi.org/10.1073/pnas.1313731110.

Vangay, P., A. J. Johnson, T. L. Ward, G. A. Al-Ghalith, R. R. Shields-

Cutler, B. M. Hillmann, S. K. Lucas, et al. “US Immigration Westernizes
the Human Gut Microbiome.” Cell 175, no. 4, (2018): 962–972.
https://doi.org/10.1016/j.cell.2018.10.029.

48
The Microbiome
and Metabolic Health
7
Early research suggested that a person’s gut
microbes could predispose them to developing
obesity. For a short time, researchers used the
ratio of two bacterial phyla, Firmicutes and
Bacteroidetes, as a biomarker for obesity and other
metabolic diseases; a lower F/B ratio was assumed
to predict obesity. The F/B ratio was based on a
groundbreaking study that used FMT from rodents
or humans with obesity to germ-free rodent
recipients, which rapidly developed obesity after the
transplant. These studies strongly suggested that the
microbiome played a causal role in weight gain. But
this ratio was quickly revealed to be unreliable, in part
because a phylum contains hundreds or thousands of
microbial species that all behave differently. Improved
study methods and designs have since shown that
the trillions of microorganisms living inside your
gut play a crucial role in weight regulation and
metabolism, as you’ll learn in this lecture.

49
 7. The Microbiome and Metabolic Health

Metabolic Health
Metabolic health refers to the body’s ability to regulate blood glucose levels,
maintain healthy lipid profiles, and effectively utilize energy through a series
of complex chemical reactions that are often referred to as metabolism. A
metabolically healthy person will have metabolic flexibility, or the capacity
to switch between different fuel sources—like fats or carbohydrates—for
energy. For example, during high-intensity exercise, your muscles rely mostly
on glucose as an energy source because it can be broken down rapidly. While
you’re sleeping, however, your body can rely more on slowly metabolizing its
stored fats for energy and reserve the glucose for more urgent energy needs.

Metabolic disease refers to a group of disorders caused by abnormalities in

these chemical reactions. Type 2 diabetes, for example, occurs when the
body’s cells become resistant to the hormone insulin or when the pancreas
can’t produce enough insulin to keep up with the incoming glucose. When
this happens, glucose can’t be transported from the blood into the cells, which
leads to elevated blood sugar. If left untreated, type 2 diabetes can lead to
other health problems, like nerve or kidney damage.

So, what role does the microbiome play in metabolic health? One interesting
finding has to do with energy balance. This is the difference between
the energy your body absorbs from food and the energy it expends in the
operations of day-to-day life: moving, pumping blood, thinking, and so on.
Put simply, energy balance is a function of energy in versus energy out. Some
relatively recent studies have lead researchers to believe that the microbiome
factors into this metabolic equation.

Short-Chain Fatty Acids

A large portion of your gut microbes ferment carbohydrates to harness energy
for themselves. In the process, they produce SCFAs, such as butyrate, acetate,
and propionate. The SCFAs produced by this process can then be metabolized
by the human body as a form of caloric energy. This is called energy
harvesting. Gut microbes convert one source of energy that isn’t accessible

50
 7. The Microbiome and Metabolic Health

to humans (like the calories stored in dietary fiber) into a source that can be
used by the human host (like butyrate.) This essentially makes more calories
available from the diet, which can impact energy balance.

Research in this area is still new, however, and it’s unclear whether the
conversion of fiber to SCFAs always results in higher energy absorption,
as some of those SCFAs can be excreted in feces. In other words, microbes
might make more energy available through SCFAs, but the body may or may
not absorb that energy. Also, there isn’t a clear correlation between fecal or
circulating SCFA content and body weight. So, even if your microbiome is
particularly active when it comes to energy harvesting, it doesn’t mean that
you’ll be predisposed to weight gain or have difficulty losing weight.

The body also uses these SCFAs in varying ways. SCFAs can be absorbed like
dietary fats, but they can also bind to receptors on intestinal cells. Unlike
larger fatty acids, they can circulate freely in the bloodstream and cross the
blood-brain barrier. This allows them to bind to receptors on a variety of cells,
including muscle and fat cells, where they act more like chemical messengers
than absorbable nutrients.

Although the mechanisms aren’t completely understood and much of the

research is still limited to rodent models, there are a few ways SCFAs have
been shown to regulate metabolism, hunger, and appetite. First, they can
affect how quickly food travels through the digestive tract. This so-called
transit time can impact energy balance because if food passes more quickly
through your digestive system, you will tend to absorb fewer nutrients.
SCFAs can also modify the release of hunger and satiety hormones, and they
influence the production of thyroid hormones, which regulate metabolism.
They can even act on areas of the brain, such as the hypothalamus, to reduce
appetite or food reward, which is the pleasure we experience when eating
something tasty.

Researchers are still a long way from implicating any specific microbes
or a specific “blend” of SCFAs necessary to assert control over hunger or
appetite. But one recent study has shed some light on how much energy the
gut microbiome might harvest based on someone’s diet. Researchers placed
a group of healthy adults into a metabolic chamber where they could tightly
control and measure their energy balance, including the energy lost in their

51
 7. The Microbiome and Metabolic Health

feces. Each participant ate either a Westernized diet or a minimally processed,

fiber-rich diet for 6 days. Then, they took a 2-week break. When they
returned, participants switched to the other diet and followed that for 6 more
days. Each diet provided enough calories for weight maintenance, and all of
the macronutrient content was matched, except fiber (which was higher in the
minimally processed diet).

Researchers found that the participants’ microbes harvested more energy

from the minimally processed diet. In other words, the microbes produced
more SCFAs on the minimally processed diet compared to the Westernized
diet. This made sense considering that the gut microbes had access to more
dietary fiber. However, more energy was lost in feces when the participants
followed the minimally processed diet. Although they produced and
absorbed more SCFAs, they were in a slight caloric deficit of about 116
calories per day, on average (range: 60 to 172 calories). While following the
Westernized diet, however, they absorbed nearly all of the available energy.
Also, participants lost more weight after following the minimally processed
diet compared to the Westernized diet (0.6 kilograms versus roughly 130
grams, respectively).

Many energy-harvesting microbes are considered beneficial (or neutral), and

SCFAs provide several different benefits. For instance, it’s believed that they
have anti-inflammatory effects, support the immune system, and promote
heart health. So, you shouldn’t think of energy harvesting as a harmful
process. It’s simply another factor to consider if you’re seeing some unexpected
results based on your expected energy balance.

The Microbiome and Weight

While the gut microbiome doesn’t predict weight loss (or weight gain), there
is some evidence that it could play a role in the common phenomenon of
weight regain. Much of this evidence has come from studying changes in
the microbiomes of people who have lost weight by following a weight loss
diet. These studies often reveal that dietary changes don’t totally reshape
the gut microbiome. A person’s gut microbiome is relatively stable through
adulthood.

52
 7. The Microbiome and Metabolic Health

One study investigated changes in the microbiome immediately after a period

of weight loss. Researchers theorized that the temporary gut microbiome of
the post-weight loss phase might help the participants maintain their weight
loss. They used an autologous fecal transplant, treating participants with
their own post-weight-loss fecal samples for 6 months after completing their
weight loss intervention. But this only helped to maintain the new, lower body
weight in the participants whose microbiomes changed significantly during
weight loss.

There’s more evidence that a microbiome’s baseline composition doesn’t

affect your ability to maintain weight loss. Rather, weight loss might depend
more on the microbiome’s day-to-day variability and its responsiveness
to dietary changes. In one study, researchers gave participants one of two
diets to follow: one low fat and the other low carbohydrate. The weight loss
results varied depending on how responsive or variable each participant’s
microbiome was. A low-fat diet led to more weight loss in participants whose
microbiomes varied a lot day to day while they were following the diet. Those
on a low-carbohydrate diet, though, tended to lose more weight if their
microbiome responded strongly to the new diet, changing a lot initially but
then remaining stable day to day. In other words, weight loss maintenance
reflected both how dynamic or stable the microbiome was and the diet that
the participants were on. But no one’s baseline microbiome stood out as
particularly predictive of weight loss maintenance.

When it comes to metabolism, your gut microbiome can affect more than
just weight regulation. Certain gut microbes also release an endotoxin
called lipopolysaccharide (LPS). Sometimes, elevated levels of LPS enter
the bloodstream, causing a condition called metabolic endotoxemia. When
endotoxins enter the bloodstream, they can activate the immune system,
triggering an inflammatory response. This inflammation has been linked to
various health problems, including insulin resistance, type 2 diabetes, obesity,
cardiovascular disease, and nonalcoholic fatty liver disease. In addition,
excessive exposure to endotoxins can overwhelm the liver’s detoxification
pathways, leading to liver damage and dysfunction.

Metabolic endotoxemia has been linked to a high-fat, high-sugar diet and

increased intestinal permeability, sometimes referred to as “leaky gut.” A
more permeable intestine can allow more LPS to enter the bloodstream,

53
 7. The Microbiome and Metabolic Health

which raises the risk for metabolic endotoxemia. And intestinal permeability
is associated with several of the health problems mentioned previously.
However, scientists still don’t know whether the intestinal permeability is a
cause or consequence of the disease or if there is perhaps some feedback loop
perpetuating each one. In any case, you’ll get the greatest benefits from eating
a minimally processed, plant-forward diet and limiting alcohol intake.

READING
Brüssow, H. “Problems with the Concept of Gut Microbiota
Dysbiosis.” Microbial Biotechnology 13, no. 2 (2020): 423–434.
https://doi.org/https://doi.org/10.1111/1751-7915.13479.

Cani, P. D., E. Moens de Hase, and M. van Hul. (2021). “Gut Microbiota and Host
Metabolism: From Proof of Concept to Therapeutic Intervention.” Microorganisms 9, no.
6 (2021). https://doi.org/10.3390/microorganisms9061302.

Corbin, K. D., E. A. Carnero, B. Dirks, D. Igudesman, F. Yi, A. Marcus, et al.

“Host-Diet-Gut Microbiome Interactions Influence Human Energy Balance:
A Randomized Clinical Trial.” Nature Communications 14 (2023): 3161.
https://doi.org/10.1038/s41467-023-38778-x.

Fragiadakis, G. K., H. C. Wastyk, J. L. Robinson, E. D. Sonnenburg, J. L. Sonnenburg,

and C. D. Gardner. “Long-Term Dietary Intervention Reveals Resilience of the Gut
Microbiota Despite Changes in Diet and Weight.” American Journal of Clinical Nutrition
111, no. 6 (2020): 1127–1136. https://doi.org/10.1093/ajcn/nqaa046.

Gong, J., Y. Shen, H. Zhang, M. Cao, M. Guo, J. He, B. Zhang, et al. “Gut Microbiota
Characteristics of People with Obesity by Meta-Analysis of Existing Datasets.” Nutrients
14, no. 14 (2022): 2993. http://dx.doi.org/10.3390/nu14142993.

Grembi, J. A., L. H. Nguyen, T. D. Haggerty, C. D. Gardner, S. P. Holmes, and J.

Parsonnet. “Gut Microbiota Plasticity Is Correlated with Sustained Weight Loss on a
Low-Carb or Low-Fat Dietary Intervention.” Scientific Reports 10, no. 1 (2020): 1405.
https://doi.org/10.1038/s41598-020-58000-y.

Lahtinen, P., A. Juuti, M. Luostarinen, L. Niskanen, T. Liukkonen, J. Tillonen, J. Kössi, et

al. “Effectiveness of Fecal Microbiota Transplantation for Weight Loss in Patients with
Obesity Undergoing Bariatric Surgery: A Randomized Clinical Trial.” JAMA Network
Open 5, no. 2 (2022): e2247226. https://doi.org/10.1001/jamanetworkopen.2022.47226.

54
 7. The Microbiome and Metabolic Health

Ojo, O., Q. Q. Feng, O. O. Ojo, and X. H. Wang. “The Role of Dietary Fibre in
Modulating Gut Microbiota Dysbiosis in Patients with Type 2 Diabetes: A Systematic
Review and Meta-Analysis of Randomised Controlled Trials.” Nutrients 12, no. 11
(2020): 3239. https://doi.org/10.3390/nu12113239.

Perna, S., Z. Ilyas, A. Giacosa, C. Gasparri, G. Peroni, M. A. Faliva, C. Rigon, et al. “Is
Probiotic Supplementation Useful for the Management of Body Weight and Other
Anthropometric Measures in Adults Affected by Overweight and Obesity with
Metabolic Related Diseases? A Systematic Review and Meta-Analysis.” Nutrients 13, no.
2 (2021): 666. https://doi.org/10.3390/nu13020666.

Rinott, E., I. Youngster, A. Y. Meir, G. Tsaban, A. Kaplan, H. Zelicha, E. Rubin, et al.

“Autologous Fecal Microbiota Transplantation Can Retain the Metabolic Achievements
of Dietary Interventions.” European Journal of Internal Medicine 92 (October 2021):
17–23. https://doi.org/10.1016/j.ejim.2021.03.038.

55
The Gut-Muscle
Axis and Exercise
8
You might think that the benefits of exercise are all
about building muscle, shedding fat, and boosting
your cardiovascular health. But did you know
that your gut bacteria might also be getting in on
the action? Recent studies have shown that the
trillions of microorganisms in your gut can play a
crucial role in how your body responds to physical
activity, influencing everything from energy levels
to recovery time. In this lecture, you’ll discover
the surprising ways in which exercise and the gut
microbiome are intertwined.

56
 8. The Gut-Muscle Axis and Exercise

The Gut-Muscle Axis

Intense physical activity exerts mechanical and chemical stressors on the GI
tract. Exercise directs blood flow to working muscles and increases activity
in the sympathetic nervous system. In turn, these changes modulate the pH,
oxygen levels, and nutrient availability in the gut. Because the microbiota
play integral roles in nutrient assimilation, immune activity, and metabolic
flexibility, they are an obvious target for research into exercise performance. The
gut-muscle axis—the bidirectional communication between the gut microbiome
and the skeletal muscle system—is a fairly recent discovery in microbiome
science. It’s through this pathway that the microbiome could influence muscle
metabolism, age-related muscle loss, and even athletic performance.

Metabolic endotoxemia is one link between the microbiome and muscle

metabolism. Remember that this refers to the chronic, low-grade
inflammation linked to endotoxins from certain microbes, particularly an
overabundance of LPS in the blood. When LPS binds to immune receptors
on skeletal muscle cells, it starts an inflammatory cascade, which may lead to
metabolic inflexibility and mitochondrial dysfunction. In other words, gut
microbes can produce endotoxins that cause skeletal muscle to become both
insulin resistant and worse at breaking down fats for energy, meaning that
more glucose remains in circulation, and fats are stored in the muscle cell
instead of fat cells. These abnormalities are linked to metabolic diseases like
type 2 diabetes.

57
 8. The Gut-Muscle Axis and Exercise

Human studies have also investigated the relationship between the gut
microbiome and muscle function in older adults, who will begin to experience
sarcopenia, or age-related muscle loss, around the age of 50. Interestingly,
older adults also lose microbial diversity over time, but certain microbes, like
Akkermansia muciniphila, have been linked to better muscle function and
physical performance in this population. So, both muscle metabolism and
age-related muscle loss and performance seem to have a relationship with the
microbiome.

A recent systematic review examined the impact of exercise on the gut

microbiome in various species, including rodents, dogs, horses, and humans.
Despite the lack of standardization of diet, training methodology, or
microbial analysis in these studies, some trends emerged. In the rodent
studies, the effects of exercise were examined using diets ranging from
25% to 60% calories from fat in models of health, obesity, type 2 diabetes,
cardiovascular disease, and metabolic syndrome, both with and without
control groups.

In a forced swim test, mice with a complete microbiome had better endurance
than those with a single beneficial strain, which in turn performed better than
those with no bacteria. Forced treadmill running either had no effect on the
microbiome or marginally increased or decreased the abundance of some strains.

58
 8. The Gut-Muscle Axis and Exercise

However, the caveat here is the amount of intense exercise that the mouse
does. Compared to a mouse’s voluntary activity, the volume of forced treadmill
running is extremely low. Voluntary wheel running studies have shown an
increase in bacteria that produce the beneficial SCFA butyrate. Differing
microbial responses to exercise may also depend on age, as older rodents exhibit
less change in diversity after exercise compared to younger rodents.

Observational studies of people across the spectrum of physical activity—

from recreational exercisers to competitive athletes—have shown that those
with higher levels of fitness also have more diverse microbiomes enriched with
beneficial butyrate-producing microbes. While human intervention studies
are limited, the majority have focused on endurance exercise. These studies
have observed changes from baseline, including variations in several taxa
and gene expression after completion of a marathon. In longer-term studies,
adding an hour of cycling, walking, boat racing, or concurrent endurance
and resistance training resulted in heterogeneous results. This suggests that
the type and intensity of exercise might also exert different effects on the gut
microbiome, but no clear patterns have emerged.

Both cardio and resistance training offer benefits to gut health, albeit through
different mechanisms, and the effects of cardio are probably more direct.
Cardiovascular exercise has been shown to increase gut microbiome diversity,
while resistance training can affect muscle mass, which in turn impacts
metabolic pathways related to gut health. That being said, the majority of
research on exercise and the gut microbiome has focused on aerobic activity.
At the moment, researchers don’t know what effect resistance training has
on its own.

Bacteria and Exercise

When it comes to overall health, the American College of Sports Medicine
recommends at least 150 minutes of moderate aerobic exercise and at least 2
days of resistance training per week. Intervention studies have also provided
some evidence that the microbiome you have when you start a new exercise
routine might influence how it changes and could even influence how much
your muscles respond to the training.

59
 8. The Gut-Muscle Axis and Exercise

Currently, a few groups of bacteria have been consistently linked with exercise,
including species found within the Prevotella, Akkermansia, Lactobacillus,
Lachnospiraceae, and Ruminococcus groups. These groups appear to be either
enriched in physically active individuals, associated with cardiovascular
fitness, or increased after an exercise intervention. However, evidence suggests
that these changes are transient. Within a few weeks after completing the
exercise intervention, the number of these species return to the baseline.

A key question is whether the microbiome influences exercise performance—

or the other way around. Rodent intervention studies could suggest the
directionality of this dynamic. Earlier, you saw that mice with a complete
microbiome fared much better during forced endurance tests compared to
those that had no gut bacteria or a single beneficial strain.

Food, Your Microbiome, and Exercise

Additionally, a relationship between diet, the microbiome, and exercise has
emerged in recent years based on data examining the dietary patterns and
microbial profiles of endurance and resistance-trained athletes. Most athletes
consume a diet higher in carbohydrates and protein compared to sedentary
people, so it is a challenge to determine the effect of diet or exercise alone. But
some studies have shown that exercise and dietary fiber may have the greatest
impact on the gut microbiome when they’re provided simultaneously. It’s
possible that, without a proper diet, exercise may not affect the microbiome
much at all.

For example, in one study, bodybuilders whose diets were fiber deficient had
microbiomes that resembled those of sedentary participants, while those
eating adequate fiber had more diverse microbiomes. Observational data have
also illustrated an inverse relationship between dietary protein intake and
overall diversity in endurance athletes—the more protein, the less diversity,
although the lower diversity could also have been attributed to low fiber
intake. These findings hint that a fiber-deprived microbiome may not have
the capacity to respond to an exercise intervention because many of the
microbes associated with cardiovascular fitness rely heavily on fermenting
fiber to produce energy.

60
 8. The Gut-Muscle Axis and Exercise

Soluble fiber dissolves in water to form a gel-like substance and helps lower
cholesterol and stabilize blood sugar levels. It’s also the preferred energy source
for your gut microbes because most soluble fibers are highly fermentable. It’s
found in various foods, like oats, beans, and lentils. Insoluble fiber doesn’t
dissolve in water and isn’t readily fermentable, but it adds bulk to your
stool. It’s found in a variety of fruits and vegetables. Both types of fiber are
beneficial for gut health, but soluble fiber has a more direct impact on the gut
microbiome by serving as a prebiotic. It slows transit time and allows stool
to absorb more water, making it easier to pass. Insoluble fiber speeds up the
passage of stool, supporting regularity. As for the best way to get fiber, whole
foods are generally superior to supplements for their additional nutrients and
better bioavailability.

Fiber and Physical Activity

There is some evidence that certain microbes could play a role in exercise
performance. More recent studies have combined human studies with rodent
fecal transplant models. They’ve identified microbes of interest in humans
and then used FMTs to measure their effects on rodent exercise performance.

In one study, endurance runners were supplemented with alpha-cyclodextrin,

which is a carbohydrate similar to resistant starch, one of the favorite foods of
gut bacteria. The supplement was linked to improved performance and higher
levels of Bacteroides uniformis. When researchers transplanted that microbe
into mice, their exercise performance improved, too. The researchers believe
that the microbe might play a role in glucose metabolism, which makes more
fuel available during endurance exercise.

In a similar study, fecal samples were taken from elite runners after they
completed a marathon. These runners were found to have higher-than-average
levels of the genus Veillonella in their stool. Researchers transplanted a strain
of Veillonella into mice and found that they were able to run longer. It seems
that at least some strains in this genus can convert lactate—a product of
energy production from glucose—to propionate, which reduces the amount of
energy the body needs to clear lactate.

61
 8. The Gut-Muscle Axis and Exercise

Probiotic supplements that introduce strains of beneficial bacteria haven’t

shown much promise for improving performance in any sport so far.
However, in some cases, they could improve recovery and support an athlete’s
immune system to prevent them from taking unplanned breaks due to illness.
Of course, it’s not as simple as exercising your way to a resilient microbiome or
shaving minutes off of your mile time with the right probiotic. Rodent models
are useful for explaining mechanisms in isolation, but they can’t accurately
represent the complexity of the human gut microbiome. In addition, most of
these studies were observational, so they examined correlation, not causation.
And almost none controlled for diet, which often differs between athletes
and sedentary people and has a significant impact on the gut microbiome.
However, the findings do provide support for the following statement: Fiber
and physical activity are important both for you and your gut microbiome.

READING
Bycura, D., A. C. Santos, A. Shiffer, S. Kyman, K. Winfree, J. Sutliffe, T. Pearson, et al.
“Impact of Different Exercise Modalities on the Human Gut Microbiome.” Sports 9, no.
2 (2021): 14. https://doi.org/10.3390/sports9020014.

Clauss, M., P. Gérard, A. Mosca, and M. Leclerc. “Interplay between Exercise and Gut
Microbiome in the Context of Human Health and Performance.” Frontiers in Nutrition
8 (2021). https://doi.org/10.3389/fnut.2021.637010.

Estaki, M., J. Pither, P. Baumeister, J. P. Little, S. K. Gill, S. Ghosh, Z. Ahmadi-

Vand, et al. “Cardiorespiratory Fitness as a Predictor of Intestinal Microbial
Diversity and Distinct Metagenomic Functions.” Microbiome 4 (2016): 42.
https://doi.org/10.1186/s40168-016-0189-7.

Jäger, R., A. E. Mohr, K. C. Carpenter, C. M. Kerksick, M. Purpura, A. Moussa, J.

R. Townsend, et al. “International Society of Sports Nutrition Position Stand:
Probiotics.” Journal of the International Society of Sports Nutrition 16, no. 1 (2019): 62.
https://doi.org/10.1186/s12970-019-0329-0.

Mitchell, C. M., B. M. Davy, M. W. Hulver, A. P. Neilson, B. J. Bennett, and

K. P. Davy. “Does Exercise Alter Gut Microbial Composition? A Systematic
Review.” Medicine & Science in Sports & Exercise 51, no. 1 (2019): 160–167.
https://doi.org/10.1249/MSS.0000000000001760.

62
 8. The Gut-Muscle Axis and Exercise

“Bacteroides uniformis and Its Preferred Substrate, α-cyclodextrin, Enhance Endurance

Morita, H., C. Kano, C. Ishii, N. Kagata, T. Ishikawa, A. Hirayama, Y. Uchiyama, et al.

Exercise Performance in Mice and Human Males.” Science Advances 9, no. 4 (2023):
eadd2120. https://doi.org/10.1126/sciadv.add2120.

Rodriguez, J., A. M. Neyrinck, M. van Kerckhoven, M. A. Gianfrancesco, E. Renguet,

L. Bertrand, P. D. Cani, et al. “Physical Activity Enhances the Improvement of
Body Mass Index and Metabolism by Inulin: A Multicenter Randomized Placebo-
Controlled Trial Performed in Obese Individuals.” BMC Medicine 20 (2022): 110.
https://doi.org/10.1186/s12916-022-02299-z.

Scheiman, J., J. M. Luber, T. A. Chavkin, T. MacDonald, A. Tung, L.-D. Pham, M.

C. Wibowo, et al. “Meta-omics Analysis of Elite Athletes Identifies a Performance-
Enhancing Microbe That Functions via Lactate Metabolism.” Nature Medicine 25
(2019): 1104–1109. https://doi.org/10.1038/s41591-019-0485-4.

Son, J., L. G. Jang, B. Y. Kim, S. Lee, and H. Park. “The Effect of Athletes’ Probiotic Intake
May Depend On Protein and Dietary Fiber Intake.” Nutrients 12, no. 10 (2020): 2947.
https://doi.org/10.3390/nu12102947.

Torquati, L., T. Gajanand, E. R. Cox, C. R. G. Willis, J. Zaugg, S. E. Keating, and J. S.

Coombes. “Effects of Exercise Intensity on Gut Microbiome Composition and Function
in People with Type 2 Diabetes.” European Journal of Sport Science 23, no. 4 (2023):
530–541. https://doi.org/10.1080/17461391.2022.2035436.

63
The Gut-Brain
Axis and Mood
9
You might be wondering what the brain has to do
with gut health. Have you ever felt butterflies in
your stomach when you’re nervous? Perhaps your
stomach feels upset when you’re stressed. Believe
it or not, your gut and brain are closely connected,
and this connection is known as the gut-brain axis,
which involves a complex network of signals and
pathways that facilitate two-way communication
between the GI tract and the central nervous
system. In this lecture, you’ll explore the intricacies
of this connection and its importance to bodily
functions and mental health.

64
 9. The Gut-Brain Axis and Mood

Your Nervous System

The nervous system is a complex system of specialized cells that transmits
information to many parts of your body, allowing you to coordinate your
actions and move. On a basic level, the nervous system is composed of two
types of cells: neurons and glial cells. Neurons transmit messages across the
body, and glial cells protect and maintain neurons. The “messages” that
neurons send are both chemical and electrical, and they are sent to other
neurons or cells using special junctions called synapses. The chemical signals
that cross these synapses are neurotransmitters. Neurotransmitters, including
serotonin and dopamine, aid in a host of biological functions, such as sleep,
heart rate, movement, and even thinking.

Your nervous system can be divided into the central nervous system and
the peripheral nervous system. Your brain and spinal cord make up your
central nervous system. Your brain is like the central control hub for every
bodily function—it processes incoming sensory information and sends
out instructions to the peripheral nervous system, which covers all of the
nervous cells outside of your brain and spinal cord. The main function of
the peripheral nervous system is to connect the central nervous system with
the rest of the body, like a relay station. It can also be broken down into two
parts: the somatic nervous system and the autonomic nervous system.

The somatic nervous system connects your central nervous system to your
skeletal muscles, and it’s mostly under voluntary control. It also transmits
tactile sensory information, like heat, texture, or pain, to your central nervous
system. The autonomic nervous system, however, acts largely unconsciously
and automatically. It regulates your internal organs to control things like heart
rate, breathing, digestion, arousal, and the fight-or-flight response. It can also
be separated further into the sympathetic and parasympathetic branches.

The sympathetic branch stimulates the fight-or-flight response, or a

physiological reaction to danger. It primes the body to either fight or escape
by releasing neurotransmitters that release glucose into the bloodstream
and route more blood to the muscles. Some functions, like digestion, are
paused when the sympathetic nervous system is active. In contrast, the
parasympathetic nervous system is more active during periods of rest and

65
 9. The Gut-Brain Axis and Mood

digestion. Both branches of the autonomic nervous system are always active,
but one might be more active depending on what you’re doing, like going for a
run versus sitting down to eat.

When it comes to gut health, the enteric nervous system is even more
fascinating. It is a group of nerves that runs along your digestive tract from
your esophagus to your anus, and it’s sometimes called the second brain
because it can operate independently of your brain and spinal cord. It controls
the movement of food through your digestive tract. When you eat, your
stomach and intestines need to contract to move the food along. The enteric
nervous system coordinates this process by sending signals to the muscles in
your digestive tract. Moreover, nerves in your enteric nervous system sense the
presence of food in your digestive tract and signal your body to produce the
right blends of digestive juices and enzymes. This nervous system can even
sense when something is wrong with your digestive tract. For example, if there
is an infection, it can send signals to your immune system to help fight it off.

The Gut-Brain Axis

The enteric nervous system, the autonomic nervous system, the gut
microbiota, and all of the associated neurotransmitters and hormones
combine to form the gut-brain axis. This is a two-way communication
highway that connects your digestive system with your brain. It uses various
signaling pathways to communicate, including hormones, neurotransmitters,
and immune cells. Much of this bidirectional communication travels along
the vagus nerve, a major parasympathetic nerve that extends from the
brainstem to the abdomen. The vagus nerve transmits signals between the
gut and the brain, allowing the brain to regulate gut function and the gut to
influence brain activity.

The gut-brain axis plays a potentially important role in many bodily

functions. It aids in digestion, regulating the movement of food through the
digestive tract and the secretion of digestive enzymes and hormones. And it
plays a role in immune response, recruiting immune cells to fight infection
and inflammation in the gut. The gut-brain axis also aids in maintaining
the balance of the gut microbiome, and it could influence your mood and

66
 9. The Gut-Brain Axis and Mood

emotions. Many neurotransmitters are produced in the gut, some of which

can enter the brain, and researchers believe that this is one way the gut
microbiota could play a role in mood disorders and mental health.

The co-occurrence of psychiatric and GI symptoms is quite common. About

half of patients with a functional GI disorder experience psychiatric symptoms,
and a similar percentage of psychiatric patients are diagnosed with IBS. But
do gut bacteria play a role in mood disorders? The evidence is inconclusive.
Certain types of bacteria produce substances that affect the nervous system,
like neurotransmitters and neuromodulators. For example, some bacteria, such
as Enterococcus, can produce serotonin. Serotonin derived from the gut plays
a role in the movement of the digestive system and can affect how quickly the
stomach empties and feelings of fullness. However, researchers have not seen
this serotonin cross the blood-brain barrier and directly influence mood.

There’s a bit more evidence that the gut-brain axis may play a role in GI
distress. This has been researched in patients who suffer from various
clinical GI conditions, including IBS and IBD. For example, studies have
shown that alterations in the gut microbiome and abnormal enteric nervous
system activity could contribute to IBS symptoms like abdominal pain and
dysregulated GI motility. There’s also some evidence that psychological stress
is strongly associated with IBS symptoms.

Recent evidence also indicates that the microbiome could enhance or suppress
hunger and appetite via the gut-brain axis and the endocannabinoid system.
This system helps regulate intestinal permeability and eating behaviors.
Endocannabinoids are lipid-based neurotransmitters produced by the body
in response to various physiological signals. They help regulate a wide range
of functions, including mood, pain perception, appetite, inflammation,
and immune response. Theoretically, if the endocannabinoid system
becomes overactive, it could increase the desire for pleasure-driven eating
while reducing the appetite-suppressing effects of a hormone called leptin.
Simultaneously, it could compromise the integrity of the intestinal barrier,
which may contribute to metabolic endotoxemia.

A high-fat diet and obesity have been linked to increased activity of the
endocannabinoid system and changes in the gut microbiome. These factors
may contribute to hedonic eating (eating for pleasure rather than hunger) and
disrupted fat metabolism. Obesity is associated with higher endocannabinoid

67
 9. The Gut-Brain Axis and Mood

levels in the blood and fatty tissues as well as increased receptor expression.
Consuming high-fat foods appears to increase endocannabinoid production
in the intestines and slow the rate at which endocannabinoids are broken
down. Individuals with eating disorders or psychiatric symptoms often exhibit
disrupted appetite, disrupted signaling of fullness, and altered eating behaviors.

The Microbiome and Mental Health

There’s some evidence that psychological aspects of disordered eating could
influence the microbiota. Specifically, psychological stress, both chronic
and experienced early in life, has been shown to reduce microbial diversity
in animals.

Research on the microbiome’s connection to anxiety and depression is limited,

but animal studies have turned up some compelling findings. Scientists have
conducted experiments where they transferred fecal matter between mice with
different personalities or studied mice that lacked a microbiome altogether.
These studies have shown a link between the microbiome and anxiety. In
one experiment, researchers transferred fecal matter between anxious and
aggressive mice, and their personalities changed accordingly. Aggressive
mice became more docile, while anxious mice became more exploratory.
This suggests that the microbiome can have a significant influence on mouse
behavior, even more so than their genes. Similar results were observed in
germ-free mice that received fecal transplants from human donors diagnosed
with major depressive disorder. Their behavior changed after the transplant,
indicating that the microbiome might also play a role in human mental health.

Studies of mice have also suggested that the microbiome may impact the
production of substances that support cognitive function. For example,
although the exact mechanisms are unclear, the microbiome might affect
levels of brain-derived neurotrophic factor, which is important for brain
development, as well as levels of GABA, a neurotransmitter that regulates
mood. However, note that the data from rodent studies are limited in their
application to human biology. The germ-free mice used do not develop fully
functioning immune or nervous systems, making them inadequate models for
human physiology.

68
 9. The Gut-Brain Axis and Mood

Recent studies have shown that the gut microbiome can influence the
function of the kynurenine pathway, which plays an important role in the
metabolism of tryptophan. Tryptophan is an essential amino acid obtained
from our diet. The body metabolizes it to produce various molecules,
including proteins, neurotransmitters, and other neuroactive compounds,
such as quinolinic acid, which has an excitatory effect, or kynurenic acid,
which can reduce signaling in the brain.

Changes in the kynurenine pathway could have significant implications

for mood and mental health. For example, such alterations could reduce
the availability of serotonin, which plays a crucial role in regulating mood.
Tryptophan is also a precursor for serotonin, and when tryptophan is diverted
toward the kynurenine pathway instead of toward serotonin synthesis, it
can lead to reduced serotonin levels, which are often observed in individuals
with depression. Certain bacteria in the gut have the ability to break down
tryptophan and produce metabolites that can influence the activity of
enzymes in the kynurenine pathway.

69
 9. The Gut-Brain Axis and Mood

The Microbiome and Medications

Antidepressants are among the top three most prescribed and used therapeutic
drug classes. While there’s limited research on the effects of antidepressants
on the gut microbiota, some preclinical studies are available. For example,
one study looked at selective serotonin reuptake inhibitors (SSRIs)—one
of the most commonly prescribed antidepressants. When researchers orally
administered SSRIs to animals, they found that they reduced overall
microbial diversity and decreased levels of specific taxa. Similar evidence has
been noted for tricyclic antidepressants in animal models.

However, some observational studies in humans have provided opposing

results regarding the effects of antipsychotic medications. For instance,
one study observed higher indices of diversity in patients taking the drug
risperidone, whereas another study found that diversity was lower in
patients taking other forms of second-generation antipsychotic medications.
Conflicting results like these leave researchers with no clear relationship
between the use of antipsychotic drugs, microbial changes, and treatment
outcomes or side effects. Moreover, some of these changes appear to be gender
specific, often affecting females significantly more than males, which adds an
extra layer of complexity.

There is some evidence that the gut microbiota can alter the effects of certain
neuromodulatory drugs. For instance, when Levodopa (L-dopa) is taken
orally, certain gut bacteria can convert it to a compound that isn’t neuroactive.
These microbial actions are thought to reduce the concentration of L-dopa
that is absorbed and thus possibly alter its therapeutic properties.

Note that these studies are limited by their small study sizes, heterogeneous
findings, and different definitions of “dysbiosis.” They also rely on stool
samples, which can’t represent the entire gut microbiome. At most, it can be
said that these psychotropic and neuromodulatory drugs interact with the
microbiota in a bidirectional manner: The drugs seem to have some impact
on the microbiome, and the microbiome seems to have some impact on the
drugs’ effectiveness. This two-way interaction likely accounts for some of the
variability of both the microbiome and drug efficacy between individuals.

70
 9. The Gut-Brain Axis and Mood

READING
Almeida, C., R. Oliveira, R. Soares, and P. Barata. “Influence of Gut Microbiota Dysbiosis
on Brain Function: A Systematic Review.” Porto Biomedical Journal 5, no. 2 (2020): 1–8.
https://doi.org/10.1097/j.pbj.0000000000000059.

Clark, A., and N. Mach. “Exercise-Induced Stress Behavior, Gut-Microbiota-Brain Axis

and Diet: A Systematic Review for Athletes.” Journal of the International Society of Sports
Nutrition 13, no. 1 (2016): 1–21. https://doi.org/10.1186/s12970-016-0155-6.

Cryan, J. F., and T. G. Dinan. “Mind-Altering Microorganisms: The Impact of the Gut
Microbiota on Brain and Behaviour.” Nature Reviews Neuroscience 13, no. 10 (2012):
701–712. https://doi.org/10.1038/nrn3346.

Fond, G., W. Boukouaci, G. Chevalier, A. Regnault, G. Eberl, N. Hamdani, F.

Dickerson, et al. “The ‘Psychomicrobiotic’: Targeting Microbiota in Major Psychiatric
Disorders: A Systematic Review.” Pathologie Biologie 63, no. 1 (2015): 35–42.
https://doi.org/10.1016/j.patbio.2014.10.003.

Furness, J. B. “The Enteric Nervous System and Neurogastroenterology.”

Nature Reviews Gastroenterology & Hepatology 9 (2012): 286–294.
https://doi.org/10.1038/nrgastro.2012.32.

Lee, C., E. Doo, J. M. Choi, S. Jang, H.-S. Ryu, J. Y. Lee, J. H. Oh, et al. “The
Increased Level of Depression and Anxiety in Irritable Bowel Syndrome Patients
Compared with Healthy Controls: Systematic Review and Meta-Analysis.”
Journal of Neurogastroenterology and Motility 23, no. 3 (2017): 349–362.
https://doi.org/10.5056/jnm16220.

Mayer, E. A., R. Knight, S. K. Mazmanian, J. F. Cryan, and K. Tillisch. “Gut Microbes and
the Brain: Paradigm Shift in Neuroscience.” Journal of Neuroscience 34, no. 46 (2014):
15490–15496. https://doi.org/10.1523/JNEUROSCI.3299-14.2014.

Ng, Q. X., W. Loke, N. Venkatanarayanan, D. Y. Lim, A. Y. S. Soh, and W. S. Yeo.

“A Systematic Review of the Role of Prebiotics and Probiotics in Autism Spectrum
Disorders.” Medicina 55, no. 5 (2019): 1–10. https://doi.org/10.3390/medicina55050129.

Rao, M., and M. D. Gershon. “The Bowel and Beyond: The Enteric Nervous System in
Neurological Disorders.” Nature Reviews Gastroenterology & Hepatology 13, no. 9 (2016):
517–528. https://doi.org/10.1038/nrgastro.2016.107.

Rogers, G. B., D. J. Keating, R. L. Young, M. L. Wong, J. Licinio, and S.

Wesselingh. “From Gut Dysbiosis to Altered Brain Function and Mental Illness:
Mechanisms and Pathways.” Molecular Psychiatry 21, no. 6 (2016): 738–748.
https://doi.org/10.1038/mp.2016.50.

71
Common
Digestive
10
Complaints

Perhaps you’ve noticed that your digestion feels off

lately, but you aren’t sure what’s going on. With so
much information—and misinformation—circulating
the internet, it can be confusing to pin down the
problem. Everyone will experience some form of GI
distress from time to time, and it’s nothing to feel
embarrassed about. Some of the most common
symptoms include gas, bloating, and temporary
changes in bowel habits. Today, you’ll learn about
these common GI disruptions: their causes, how to
test for them, and how to treat them.

72
 10. Common Digestive Complaints

Examining the Gut

Although bouts of GI distress are a normal part of life, there are some red flags
that could indicate the possibility of a serious illness. If you’re experiencing
the following, you should see a doctor: rectal bleeding or blood in the stool;
unexplained weight loss or fatigue; persistent abdominal pain; persistent nausea
or vomiting; a change in bowel habits (like ongoing constipation or diarrhea)
that lasts more than a few weeks; jaundice (a yellowing of the skin and eyes); and
anemia. Also, if you have a family history of GI
diseases, such as colon cancer or IBS, you
could be at increased risk, too, since
genetics could also play a role.

Since many GI diseases

share a number of
symptoms, doctors often
have to narrow down
the potential causes of
your symptoms before
arriving at the most
likely diagnosis. For
that, your doctor may
use several available
diagnostic and screening
methods to determine
the health of your GI tract.
One method is called an upper
GI series. It involves swallowing
barium—a fine powder that shows
up on x-rays. When mixed with water and
swallowed, barium coats the lining of your esophagus, stomach, and the
first part of the small intestine. The doctor can use x-ray to visualize these
structures and determine if there are any irregularities. This may be followed
by imaging of the rest of the small intestine, and in some cases, a “double
contrast” medium—like CO2—is used to show the stomach lining. This is
often used if symptoms indicate potential ulcers, tumors, or Crohn’s disease of
the small intestine.

73
 10. Common Digestive Complaints

A lower GI series includes a barium swallow followed by imaging, but it also

requires an overnight fast and bowel cleansing. It can also include a double
contrast to detect polyps, inflammation, and colon cancer. And recent
advances in medical technology have led to the development of the capsule
endoscopy, in which an individual swallows a tiny pill-sized camera that
travels the entire length of the GI tract, capturing images as it goes.

74
 10. Common Digestive Complaints

Your doctor might also conduct stool tests. For example, a fecal occult blood
test examines a stool sample for blood that isn’t apparent to the naked eye.
The blood could indicate polyps, hemorrhoids, ulcers, IBD, or other issues.
Your doctor may also test your gallbladder or pancreas since diseases affecting
these organs would lead to GI symptoms despite having a healthy digestive
tract. They might take images of your gallbladder after you eat a fatty meal or
measure the fat lost in your stool.

Breath tests are commonly used to check for small intestine bacterial
overgrowth (SIBO). When bacteria ferment specific sugars in your small
and large intestines, they produce high levels of methane and hydrogen.
Abnormally high levels of these gases in your breath can indicate an
overgrowth of bacteria or difficulty in digesting and absorbing these sugars.
Keep in mind that the accuracy of these breath tests is limited, with a
relatively high risk of producing both false positive and false negative results.
Results depend on the dose and type of sugar used, the testing center’s
reference ranges, and even the patient’s stress level. Individuals with IBS are
more likely to exhibit positive breath tests, suggesting that bacteria might play
a role in the disease. However, these results don’t have useful applications in
guiding dietary recommendations or predicting patient responses to IBS or
SIBO therapies.

Food Intolerance and Allergy

Food intolerances and allergies are both adverse reactions to food, but they
differ in their underlying mechanisms and severity. Food allergies involve
the immune system and can cause severe and potentially life-threatening
symptoms. In an allergic reaction, the immune system mistakenly identifies
a food protein as harmful and launches an attack against it. This can trigger
symptoms such as hives, swelling, difficulty breathing, and anaphylaxis.
Different types of tests can screen for or diagnose allergies, like pricking the
skin with a potential allergen. Treating a food allergy sometimes requires
strict avoidance of the allergenic food. Peanut allergies are one example that
can cause serious reactions and might require emergency treatment.

75
 10. Common Digestive Complaints

Food intolerances, however, don’t involve the immune system and are usually
less severe than allergies. They occur when the body has difficulty digesting a
nutrient due to a lack of digestive enzymes. This can cause symptoms such as
bloating, gas, diarrhea, constipation, and stomach pain. Lactose intolerance
is one common example that leads to GI distress after eating dairy. Food
intolerances are often diagnosed through a process of elimination and may
require reducing or avoiding the problematic food.

Another source of GI discomfort may be your daily protein shake or low-

carb dessert. Many “diet” products claim their diet creds by cutting sugar to
or near zero. But a lot of these products still contain sugar alcohols, which
are a type of FODMAP. In diet products, these poorly absorbed sugars, like
maltitol or sorbitol, are often used in large amounts to substitute for regular
sugar. Sugar alcohols can have a strong laxative effect, and some products are
even required to disclose this on their label.

Another common cause of gas in many health foods is inulin, a FODMAP

found in ingredients like chicory root. It’s considered a functional fiber
because it’s a concentrated, isolated indigestible carbohydrate that’s shown
some benefit for humans. However, inulin can also cause a lot of GI distress,
so check items like protein bars and powders if you think you could be
sensitive to it.

76
 10. Common Digestive Complaints

And if you drink coffee or alcohol, you could be contributing to your GI

distress. Coffee relaxes the lower esophageal sphincter, which can aggravate
heartburn. It also leads to the release of hormones like gastrin, which
increase intestinal contractions and lead to defecation in at least 30% of
the population. Alcohol consumption causes food to move through the GI
tract more rapidly, and frequent drinking can also lead to poorer nutrient
absorption as well as damage to the intestinal lining, elevated intestinal
permeability, and changes to the microbiota.

Medication and GI Issues

Although antibiotics are not typically targeted specifically at the gut
microbiota, they still have unavoidable effects when taken orally. Some can
reduce the diversity of the microbial population by up to 30%, and these
effects can last from 1 month up to 6 years. Antibiotics that target certain
types of bacteria can also affect other beneficial or neutral bacteria that
may be present. Additionally, antibiotic use can change the metabolism and
oxygen levels in the gut, which can impact the survival of the microbial
community. The use of certain antibiotics has been associated with infections
caused by C. difficile. And early or chronic antibiotic use has also been linked
to an increased risk of diseases, such as colorectal cancer, IBD, and obesity.

Nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen can cause

significant GI side effects, including GI bleeding, inflammation, ulceration,
and permeability. The risk increases with long-term use. However, only 1%
to 2% of chronic users face serious complications. And while NSAIDs can
impact gut microbiota, the relationship is complicated and highly specific to
the drug being used.

Some other drugs, like antacids and proton pump inhibitors, modify acidity
in the GI tract. While these drugs primarily reduce the acidity of the stomach,
they can also have this effect throughout the entire GI tract, especially in
the small intestine. Proton pump inhibitor use has been associated with an
increased risk of infection with C. difficile—a pathogenic bacterium that
wreaks havoc on the GI tract. It is also associated with reduced microbial
diversity as well as lower levels of certain beneficial bacterial populations, and
some evidence suggests that it may increase the risk of developing SIBO.
77
 10. Common Digestive Complaints

Laxatives can affect the microbiota, too. The laxative polyethylene glycol
(PEG) influences fluid distribution in the intestinal tract, causing a more
rapid excretion of stool. Studies on PEG use in rodents have found that it
alters various bacterial populations associated with the disruption of the
mucus barrier and immune function. Its use is also associated with increased
abundance of the genus Bacteroides, a mucin-degrading group.

Both human and rodent data provide strong evidence that the diabetes drug
metformin significantly affects gut microbiome composition. Some changes
are beneficial. For example, metformin can encourage the growth of butyrate-
producing bacteria and microbiome-specific regulation of blood glucose
levels. However, it is also associated with elevated levels of genes linked to gas
production, and it’s correlated with higher numbers of potential pathogens
and virulence factors that could actually cause diseases.

Managing Common GI Issues

One of the most effective ways to manage gas discomfort is through dietary
intervention, or managing the consumption of gas-producing foods. But did
you know that low-intensity, rhythmic exercise like walking or cycling can
also help to increase gastric motility and relieve gas discomfort? And if your
problem is excessive gas, then an over-the-counter drug like simethicone may
help by breaking up gas bubbles.

If you’re thinking of increasing your fiber intake, it’s important to do it

gradually and to give your body time to adjust. Aim for 25 to 40 grams
of fiber per day. Fiber can help with another common GI complaint:
constipation. Some foods, like green vegetables, plain yogurt, and beans,
contain specific types of fiber and fermentable carbohydrates that can make
stools softer and easier to pass. However, be cautious with supplements like
methylcellulose, which might interfere with nutrient absorption and even
cause some cramping and diarrhea. Nonfiber osmotic laxatives and stool
softeners might be helpful, but stimulant laxatives can often cause painful
cramps and disrupt normal nervous signaling.

78
 10. Common Digestive Complaints

Regarding diarrhea management, it’s important to maintain hydration

with fluids that are of equal osmolality—or particle concentration—to the
gut. Sports drinks are a common example; they’re formulated with the best
concentrations of glucose and electrolytes to facilitate absorption and prevent
GI distress. Stimulating the GI tract with food is also important to maintain
its functionality. Gradually increasing soluble fiber and resistant starch
might help thicken the stool, but it’s best to limit simple carbohydrates, sugar
alcohols, caffeine, and gas-producing foods. If you’re dealing with traveler’s
or antibiotic-associated diarrhea, you might want to consider a yeast-based
probiotic called Saccharomyces boulardii.

Probiotics
Probiotics have become massively popular as a way to address common GI
symptoms. But what’s true and what isn’t? There are generally three types
of studies that look at probiotic interventions: The first involves healthy
individuals who have no prior digestive issues, the second involves individuals
who have known digestive issues, and the third involves healthy individuals
who are given a challenge to induce digestive issues.

While these studies still lack standardized protocols, some probiotics have
been consistently effective in reducing GI distress in multiple RCTs. They
have been shown to help alleviate constipation and diarrhea associated with
antibiotic use as well as IBS, IBDs, and communicable infections. Several
have even been helpful in managing serious complications like pouchitis
and necrotizing enterocolitis and preventing intestinal infectious diseases in
children. However, note that in most cases, probiotics are used in addition to
prescribed medications.

Probiotics that have consistently shown positive results include the yeast S.
boulardii, which has been effective in preventing and treating both adult and
pediatric diarrhea associated with travel, antibiotic use, and communicable
infections, as well as in preventing C. difficile recurrence. However, the
usefulness of probiotics for reconstituting the microbiome after antibiotic
use or disease is still questionable. Some studies have even suggested that
probiotics may delay the reestablishment of the native biome after antibiotic
administration.
79
 10. Common Digestive Complaints

READING
Edakkanambeth Varayil, J., B. A. Bauer, and R. T. Hurt. “Over-the-Counter Enzyme
Supplements: What a Clinician Needs to Know.” Mayo Clinic Proceedings 89, no. 9
(2014): 1307–1312. https://doi.org/10.1016/j.mayocp.2014.05.015.

Harper, A., M. M. Naghibi, and D. Garcha. “The Role of Bacteria, Probiotics

and Diet in Irritable Bowel Syndrome.” Foods 7, no. 2 (2018): 1–20.
https://doi.org/10.3390/foods7020013.

Iriondo-DeHond, A., J. A. Uranga, M. D. Del Castillo, and R. Abalo. “Effects of Coffee

and Its Components on the Gastrointestinal Tract and the Brain-Gut Axis.” Nutrients
13, no. 1 (2020): 88. https://doi.org/10.3390/nu13010088.

Lange, K., M. Buerger, A. Stallmach, and T. Bruns. “Effects of Antibiotics

on Gut Microbiota.” Digestive Diseases 34, no. 3 (2016): 260–268.
https://doi.org/10.1159/000443360.

McFarland, L. V. “Use of Probiotics to Correct Dysbiosis of Normal Microbiota Following

Disease or Disruptive Events: A Systematic Review.” BMJ Open 4, no. 8 (2014): e005047.
https://doi.org/10.1136/bmjopen-2014-005047.

Miller, L. E., A. C. Ouwehand, and A. Ibarra. “Effects of Probiotic-Containing Products on

Stool Frequency and Intestinal Transit in Constipated Adults: Systematic Review and
Meta-Analysis of Randomized Controlled Trials.” Annals of Gastroenterology 30, no. 6
(2017): 1–11. https://doi.org/10.20524/aog.2017.0192.

Reding, K. W., K. C. Cain, M. E. Jarrett, M. D. Eugenio, and M. M. Heitkemper.

“Relationship between Patterns of Alcohol Consumption and Gastrointestinal
Symptoms among Patients with Irritable Bowel Syndrome.” The American Journal of
Gastroenterology 108, no. 2 (2013): 270–276. https://doi.org/10.1038/ajg.2012.414.

Suez, J., N. Zmora, G. Zilberman-Schapira, U. Mor, M. Dori-Bachash, S. Bashiardes, M.

Zur, et al. “Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by
Probiotics and Improved by Autologous FMT.” Cell 174, no. 6 (2018): 1406–1423.
https://doi.org/10.1016/j.cell.2018.08.047.

Weersma, R. K., A. Zhernakova, and J. Fu. “Interaction between Drugs and the Gut
Microbiome.” Gut 69 (2020): 1510–1519. https://doi.org/10.1136/gutjnl-2019-320204.

Yoon, M. Y., and S. S. Yoon. “Disruption of the Gut Ecosystem by Antibiotics.” Yonsei
Medical Journal 59, no. 1 (2018): 4–12. https://doi.org/10.3349/ymj.2018.59.1.4.

80
Eating for
Gut Health
11
Are you tired of scrolling through endless lists of
questionable supplements and trendy diets, all
claiming to be the secret to a healthy gut? Scroll no
further. In this lecture, based on the latest studies
and expert opinions, you will examine the foods
and supplements that have been shown to support
a thriving gut microbiome. You will also learn about
the impacts that even various dietary patterns and
eating times can have on your microbiota.

81
 11. Eating for Gut Health

Different Dietary Patterns

Your long-term dietary pattern plays a significant role in both the composition
and function of your microbiome. Diet also impacts your exposure to
health conditions like metabolic syndrome, which encompasses a group of
factors, such as high blood pressure and high cholesterol, that can lead to
heart disease, stroke, and diabetes. And it’s estimated that a prudent dietary
pattern—like the DASH diet—could reduce your risk of colorectal cancer
by about 20%. The Mediterranean dietary pattern is also linked to health
benefits and favorable changes to the gut microbiome.

The DASH and Mediterranean diets both include a wide variety of whole
grains, fruits, and vegetables, which provide fiber to gut microbes and several
plant compounds that help to regulate the body’s immune system and
inflammation. They also limit refined carbohydrates and red or processed
meats, which have been linked to an increased risk of colorectal cancer.
Instead, they recommend eating fish more often and including low-fat
dairy, both of which are associated with a reduced colorectal cancer risk.
They recommend fat sources like nuts, seeds, and olive oil, which provide
polyunsaturated fats, which can also protect against this cancer.

82
 11. Eating for Gut Health

While some research suggests that vegan or vegetarian diets are the
most protective against colorectal cancer, other findings have shown
that pescetarian diets are equally protective. These diets tend to have
more complex carbohydrates, fiber, and plant-based protein compared to
omnivorous diets, which could be why vegan diets may offer more protection
against certain heart and metabolic diseases. But omnivorous diets that
include small amounts of red meat can also be protective.

Recent studies have also looked into ketogenic diets, which are high in fat
and low in carbohydrates. According to this research, a ketogenic diet may
lead to a decrease in certain inflammatory immune cells. However, it can
also reduce the numbers of certain beneficial gut bacteria. When a ketogenic
diet is necessary for medical reasons, it can be modified to minimize the
negative effects on the gut bacteria. For example, some high-protein foods
like whey protein and pea protein promote the growth of beneficial bacteria,
and other foods high in both fat and protein—like salmon—provide omega-3
fatty acids.

Studies have also examined Paleo dietary patterns, which restrict foods to
those thought to have been eaten by our Paleolithic ancestors. Long-term,
strict adherence to a Paleo-style diet has been associated with a reduction in
beneficial gut bacteria, which may result from the low intake of fiber and
resistant starch. Paleo dieting has also been associated with elevated levels of
Trimethylamine-N-oxide, a compound produced by gut microbes that’s been
tentatively associated with cardiovascular problems. Its production may be
influenced by the duration of the diet.

Fermented Foods
Fermented foods have been consumed by humans for a long time and were
initially developed to make food last longer. However, the fermentation
process and the live bacteria present in these foods offer other potential
benefits. During fermentation, lactic acid bacteria (LAB) like Lactobacillus
are allowed to flourish as they convert carbohydrates to lactic acid, and some
strains of LAB are considered probiotic.

83
 11. Eating for Gut Health

Currently, fermented dairy products like yogurt and kefir are the only foods
considered probiotic. The World Health Organization (WHO) defines
probiotics as “live microorganisms which when administered in adequate
amounts confer a health benefit on the host.” The term adequate amounts
often refers to the presence of a significant number of live, active culture
colony-forming units (CFUs). A common benchmark is a minimum of 1
billion CFUs for it to be considered a “true” probiotic. These fermented dairy
products, as well as fermented milk from cows, goats, and camels, have higher
levels of nutrients like folate, vitamin K, and riboflavin. They also contain
compounds with antioxidant and antihypertensive properties.

So far, RCTs and epidemiological data suggest that consuming fermented

dairy products is associated with lower LDL cholesterol levels and a reduced
risk of cardiovascular disease and colorectal cancer. There is weaker evidence
suggesting that fermented dairy might improve bone mineral density,
and a few studies show potential benefits in reducing muscle soreness and
potentially improving mood.

Grains and legumes can also be fermented to produce foods like sourdough
bread, tempeh, and fermented lentils, quinoa, wheat, rye, and bran. These
products present similar benefits to fermented dairy, including increased
vitamin content, production of antioxidant and antihypertensive compounds,
and a reduction in FODMAPs. Fermented fruits and vegetables, such as
kimchi, have not been extensively studied. However, early findings suggest
similar benefits, including higher levels of phenols, many of which may have
antioxidant and anti-inflammatory effects. Emerging findings also indicate
that kimchi, gochujang, and fermented soy may improve lipid profiles.

Pro-, Pre-, and Synbiotics

Probiotic supplements, which consist of live microorganisms, can have a
positive impact on your gut and overall well-being. Although the exact
mechanisms aren’t clear, it appears that they might work by preventing the
growth of harmful bacteria, improving the integrity of our intestinal cells,
and influencing our immune and nervous systems. However, there are still
questions about whether probiotics actually colonize the digestive tracts of
those who take them and whether this matters.
84
 11. Eating for Gut Health

Recent research has shown that even if probiotic bacteria are found in fecal
samples, they may not have an impact on the tissues and the microbiota of
the gut. The location where probiotics settle and their effects are not under
our control. Due to the differences in people’s microbiomes, diets, bacterial
strains, and study designs, it is challenging to draw definitive conclusions
about the effectiveness of over-the-counter probiotics. However, studies
consistently show that probiotic supplementation can be beneficial in certain
situations, like preventing traveler’s diarrhea.

Probiotics are distinct from another common gut supplement: prebiotics.

Prebiotics are nutrients that beneficial bacteria in our gut can use as food.
They are usually in the form of fiber or carbohydrates that our bodies can’t
digest. These nutrients are fermented by microbes in our gut, producing
energy and beneficial substances called “postbiotics,” such as SCFAs. Studies
in animals and humans have shown that prebiotics can increase the numbers
of helpful bacteria like Bifidobacteria, reduce inflammation and toxins in the
body, regulate the gut’s permeability, and even affect our appetite.

You don’t necessarily need to take prebiotic supplements because these

carbohydrates are already present in many foods. Fruits, vegetables, whole
grains, nuts, and legumes contain prebiotic fibers like inulin and beta-glucan,
which promote the growth of beneficial bacteria. Resistant starch can be found
in green bananas, cooked and cooled potatoes, and rice. Studies have suggested
that consuming resistant starch may increase Bifidobacteria, lactobacilli, and
the production of butyrate while reducing inflammation markers, although
the results can vary depending on a person’s existing microbes.

85
 11. Eating for Gut Health

Synbiotics combine probiotics with prebiotics. For example, a synbiotic might

combine a specific strain of Lactobacillus and fiber. Emerging evidence suggests
that, just like probiotics, synbiotics may reduce inflammation markers in
people with obesity or IBD and improve symptoms of IBS and IBD.

Considering the limitations and high cost of probiotic and prebiotic

supplements, it is more advisable to meet the recommended daily intake of
fiber by consuming a wide variety of whole grains, fruits, vegetables, nuts, and
legumes (such as beans).

Chemicals and Additives

There’s no shortage of alarming headlines and confident influencers
proclaiming the dangers of “chemicals,” but the vast majority of these claims
are either completely fabricated or based on misinterpretations of studies done
in cell culture or animal models. Artificial sweeteners, such as acesulfame
K, aspartame, saccharin, and sucralose, have been approved by the FDA.
The safety of these sweeteners, as well as of other sweeteners like stevia and
sugar alcohols, has been extensively studied. However, their impact on the
gut microbiome is a newer area of research. Studies on cells have shown that
artificial sweeteners induce increased hormone production and inflammation.
However, these findings have not been replicated in most rodent models or in
human data. Overall, the evidence shows that artificial sweeteners are safe for
both humans and their gut microbes.

Genetically modified organisms, so-called GMOs, have also gotten a bad

reputation, but it might not be earned. Genetic modification (GM) involves
adding specific genetic material to organisms to produce desired traits, such
as resistance to insects. GM crops actually reduce the amount of pesticides
needed to protect crops, resulting in higher yields and income for farmers
and less pesticidal contamination in the end product. Studies have shown
that the effects of GM proteins on the gut microbiota are similar to those
of conventional versions, even at higher levels of ingestion. GM crops
undergo rigorous safety and allergenicity testing before they are approved for
consumption by the FDA.

86
 11. Eating for Gut Health

Food additives are substances added to improve the quality and shelf life
of foods. These additives must be authorized by government agencies and
undergo rigorous testing before being approved for use. They have set limits
on how much can be safely consumed, known as the acceptable daily intake.
Some additives are classified as generally recognized as safe (GRAS) based on
their long history of use or their inert nature. Recent studies, conducted on
rodents, have shown that some food additives and GRAS substances can lead
to intestinal inflammation, changes in the microbiota, metabolic issues, liver
abnormalities, and behavioral changes. However, these studies used rodents or
cell cultures to artificially model the human microbiome, and the doses used
were sometimes unrealistic for human consumption. So, it remains uncertain
whether these effects can be replicated in humans.

Circadian Rhythms
Gut microbiota follow the same daily rhythm as the rest of your body, called
the circadian rhythm. Disruptions in the gut microbiota, such as completely
removing them in rodents, can disrupt the daily rhythm of the host animals.
In humans, disruptions in circadian rhythm, like those caused by shift work,
are associated with metabolic syndrome. These studies suggest that the
interaction between the host and the gut microbiome is bidirectional.

Researchers are now looking into the impact of nutrient timing on circadian
rhythms. One approach gaining popularity is time-restricted eating (TRE).
This involves fasting periods and reduced meal frequency to align with
circadian rhythms and affect metabolism and inflammation. Specifically,
people who follow TRE diets will eat their meals in a restricted window,
usually between 6 and 12 hours, and fast for the rest. Studies in rodents
and a few human trials have shown that different forms of TRE can change
inflammatory markers and the gut microbiota, potentially providing
protection to the GI and nervous systems.

However, there is conflicting data suggesting that the changes may be

due to caloric restriction rather than timed eating. Starvation studies have
shown mixed results in animals and humans. Microbial diversity either
varied unpredictably or remained unchanged in response to food restriction.

87
 11. Eating for Gut Health

When changes did occur, they typically involved an increase in taxa that can
withstand low energy availability, supporting the idea that dietary changes
play a role in the effect of fasting on the microbiome. Current evidence
suggests that eating two to six meals per day, preferably during daylight hours,
including breakfast when hungry in the morning, is a good way to structure
meals for overall health and a normal circadian rhythm.

READING
Biesalski, H. K. “Nutrition Meets the Microbiome: Micronutrients and the
Microbiota. Annals of the New York Academy of Sciences 1372, no. 1 (2016): 53–64.
https://doi.org/10.1111/nyas.13145.

Cignarella, F., C. Cantoni, L. Ghezzi, A. Salter, Y. Dorsett, L. Chen, L. Fontana,

et al. “Intermittent Fasting Confers Protection in CNS Autoimmunity by
Altering the Gut Microbiota.” Cell Metabolism 27, no. 6 (2018): 1222–1235.
https://doi.org/10.1016/j.cmet.2018.05.006.

Frazier, K., and E. B. Chang. “Intersection of the Gut Microbiome and Circadian Rhythms
in Metabolism.” Trends in Endocrinology & Metabolism 31, no. 1 (2020): 25–36.
https://doi.org/10.1016/j.tem.2019.08.013.

Kaczmarek, J. L., S. V. Thompson, and H. D. Holscher. “Complex Interactions of

Circadian Rhythms, Eating Behaviors, and the Gastrointestinal Microbiota and
Their Potential Impact on Health.” Nutrition Reviews 75, no. 9 (2017): 673–682.
https://doi.org/10.1093/nutrit/nux036.

Karl, J. P., A. M. Hatch, S. M. Arcidiacono, S. C. Pearce, I. G. Pantoja-Feliciano, L. A.

Doherty, and J. W. Soares. “Effects of Psychological, Environmental and Physical
Stressors on the Gut Microbiota.” Frontiers in Microbiology 9 (September 2018): 1–32.
https://doi.org/10.3389/fmicb.2018.02013.

Lang, J. M., C. Pan, R. M. Cantor, W. H. W. Tang, J. C. Garcia-Garcia, I. Kurtz, S. L.

Hazen, et al. “Impact of Individual Traits, Saturated Fat, and Protein Source on the Gut
Microbiome.” mBio 9, no. 6 (2018): e01604-18. https://doi.org/10.1128/mBio.01604-18.

Laudisi, F., C. Stolfi, and G. Monteleone. “Impact of Food Additives on Gut Homeostasis.”
Nutrients 11, no. 10 (2019): 2334. https://doi.org/10.3390/nu11102334.

Associated with Increased Gut Microbiota α-Diversity in 3 Independent Cohorts.”

Le Roy, C., P. Wells, J. Si, J. Raes, J. Bell, and T. Spector. “Red Wine Consumption

Gastroenterology 158 (2019). https://doi.org/10.1053/j.gastro.2019.08.024.

88
 11. Eating for Gut Health

Spencer, M., A. Gupta, L. Van Dam, C. Shannon, S. Menees, and W. D. Chey.

“Artificial Sweeteners: A Systematic Review and Primer for Gastroenterologists.”
Journal of Neurogastroenterology and Motility 22, no. 2 (2016): 168–180.
https://doi.org/10.5056/jnm15206.

Suez, J., T. Korem, G. Zilberman-Schapira, E. Segal, and E. Elinav. “Non-caloric Artificial

Sweeteners and the Microbiome: Findings and Challenges. Gut Microbes 6, no. 2 (2015):
149–155. https://doi.org/10.1080/19490976.2015.1017700.

89
A Lifestyle for
Gut Health
12
When it comes to supporting gut health, your
dietary choices are an obvious place to start, but
you don’t want to forget three other important
factors: exercise, sleep, and stress management.
In today’s fast-paced society, it’s easy to put
these off because you’re overwhelmed and feel
like you don’t have time. But that’s exactly when
you need these habits the most! A prudent diet is
foundational to supporting your gut health, but the
rest of your lifestyle matters, too. As you’ll learn
in this lecture, exercise, sleep, and stress can have
a significant impact on your gut microbiome and
your overall health.

90
 12. A Lifestyle for Gut Health

Exercise and GI Issues

A growing body of research has been exploring how the microbiome could
play a role in the immune and mental-health-related benefits of regular
exercise. First, exercise has been shown to enhance immune function by
increasing the production and circulation of various immune cells, and recent
research has highlighted the role of the gut microbiome in this process.
Remember, some microbes produce metabolites like SCFAs that help regulate
the activity of immune cells, reduce inflammation, and enhance immune
surveillance. Exercise seems to encourage these SCFA-producing microbes to
flourish. So, in tandem with your gut microbiome, exercise could ultimately
promote a more robust immune system.

Research has also recently shed light on the role of the gut-brain axis in
mediating the mental health benefits of exercise. Exercise has been shown
to modulate the gut microbiome composition, increasing the abundance of
bacteria that produce various neurotransmitters. This could explain why
exercise seems to improve some of the symptoms of mood disorders like
depression and anxiety as well as IBS, which is tentatively considered to be a
disorder of the gut-brain axis.

The WHO suggests that adults between the ages of 18 and 64 perform 150 to
300 minutes of moderate-intensity aerobic physical activity each week. This
could be as simple as taking a brisk 30-minute walk each day. Alternatively,
the WHO recommends 75 to 150 minutes of vigorous-intensity aerobic
activity, like jogging, per week. If you’re a regular exerciser, you may already
be meeting or exceeding these recommendations, but you might have another
concern: the GI distress you experience after a hard training session. A
significant percentage of athletes often experience GI problems during intense
physical activity, ranging from increased gas and stomach discomfort to
nausea and even bloody diarrhea.

Exercise-associated GI distress tends to affect endurance athletes and females

more frequently. Intense exercise seems to have a particularly strong influence
on the GI tract. For example, some studies have associated GI symptoms with
exercising close to VO2 max, which is the maximum volume (V), or amount,
of oxygen (O2) that the body can utilize during exercise. The more intense the
activity, the closer you tend to get to VO2 max. One study found that even a

91
 12. A Lifestyle for Gut Health

relatively short run exceeding 60% of VO2 max can raise markers of intestinal
permeability, while intense exercise above 85% VO2 max can delay gastric
emptying, impeding the movement of food from the stomach.

Several theories attempt to explain the causes behind these issues. For
instance, elevated body temperature has been found to modify the gut
microbiome. Exercise can also temporarily deprive gut microbes of oxygen
while blood is sent to the muscles rather than the GI tract. Without oxygen,
microbes turn to anaerobic bacterial metabolism. That can subtly change
pH levels throughout the gut and potentially alter the composition of the
microbiome on a nonpermanent basis.

92
 12. A Lifestyle for Gut Health

In endurance athletes, some GI issues may also be caused by a spike in free

radicals. Free radicals are a natural result of exercise, produced when we use
oxygen to convert adenosine triphosphate to energy. But these highly reactive
molecules can damage DNA, lipids, and proteins. An overabundance of free
radicals, especially when the body struggles to get rid of them, can cause a
state called oxidative stress, which can damage gut tissues. Endurance athletes
also exhibit varying levels of endotoxins after exercise, which might be due
to temporarily elevated intestinal permeability. Although it isn’t always the
case, those that require medical attention tend to show higher markers of
inflammation and circulating endotoxins.

Limited research has explored the effects of resistance training on GI

function, but one study found impaired protein digestion and absorption
after an intense exercise session. Implementing dietary modifications, such
as following a short-term low-FODMAP diet, eating less fat before exercise,
and drinking enough carbohydrates around workouts, has shown promise
in alleviating symptoms associated with exercise-induced GI distress. It’s
important to note that all these symptoms are temporary, short-term effects.
The benefits of exercise for the gut and overall health certainly outweigh
its risks.

Gut Health and Sleep

Recent research suggests that poor sleep can have a serious impact on gut
health. Disrupted sleep patterns and insufficient sleep are linked to a variety
of digestive problems and worsening symptoms, including IBD, IBS, and
gastroesophageal reflux disease. Sleep deprivation and night shift work have
also been linked to changes in the gut microbiome, perhaps in part because
they disrupt the circadian rhythms of both the host and the microbes.
Compared to people who sleep a full 8 hours, those who get 6 or fewer tend to
have less-diverse microbiomes and higher levels of both intestinal permeability
and circulating markers of inflammation.

Establishing a regular nightly routine before bed can help you wind down and
fall asleep more quickly. Both caffeinated drinks and alcohol can prevent you
from falling asleep or reduce your sleep quality by disrupting your normal

93
 12. A Lifestyle for Gut Health

sleep cycles. Caffeine can affect your brain for several hours after you’ve
ingested it, so you may need to switch to decaf 4 to 6 hours before you plan to
go to sleep.

It’s also a good idea to avoid screens before bed and to start your routine
early enough that you have time to wind down before you actually lie down.
Consider setting a timer for about 30 minutes before you want to fall asleep,
and at that point, set your phone and other screens in another room or away
from your bed. Consider reading, journaling, or performing deep breathing
exercises along with a calming scent like lavender to relax even further. Lastly,
keep your bedroom cool and dark, as heat and humidity can disrupt sleep.

Stress
The stress response is hardwired into our bodies to help us cope with
challenging situations. However, when stress becomes chronic, it can impact
our health. For one thing, it can seriously disrupt digestion. It can prevent
the stomach from emptying or cause digestive material to pass rapidly
through the system. Chronic stress is associated with an increased risk of
developing IBS, and even short-term, or acute, stress is linked to worsening
IBS symptoms, such as increased inflammation. Anecdotally, many people
report GI distress during times of stress and anxiety, and there’s a strong link
between mood disorders like anxiety and IBS.

So, just like sleep and exercise, managing stress plays an important role in
gut health. Yoga and mindfulness-based practices to reduce stress have been
studied in patients with IBD and IBS, and both have the potential to reduce
symptoms of anxiety and depression, improve mood, and enhance quality
of life.

Sometimes, patients find that they have unhelpful thoughts and behaviors
associated with their IBS symptoms. Cognitive behavioral therapy (CBT)
can help patients address these habits and develop new ways of thinking
about their stressors. When combining CBT with other practices, such
as mindfulness, people with IBS can better understand and accept their
abdominal sensations, which can then help them manage their IBS more
effectively. Another new potential method for reducing stress to deal with GI

94
 12. A Lifestyle for Gut Health

disorders is gut-directed hypnotherapy. This involves inducing a suggestible

mental state, or hypnosis, with the help of verbal guidance from the therapist.
The aim is to facilitate receptivity to therapeutic suggestions.

There’s growing concern around how pollution and environmental toxins

may impose another form of physical stress on our bodies. Certain chemicals,
such as persistent organic pollutants (POPs), can accumulate in body tissues
and potentially cause illness. While levels of POPs in the environment have
decreased due to regulations, their effects on human health at the levels
detected are still uncertain. These environmental chemicals could potentially
affect the microbiome by interfering with enzyme activity, altering the growth
of certain bacteria, or by being metabolized by the microbiota. Some studies
have looked into these effects. However, they’ve mostly been conducted
in unrealistic doses using rodents, fish, and cell cultures. The results vary
depending on the model and chemical used and are not applicable to real-life
human exposure.

95
 12. A Lifestyle for Gut Health

The Future of Gut Research

There’s still much more to discover about the relationship between your gut
microbes and your health. For all that researchers don’t know, there’s quite a
lot that they’re learning. Consider the rapid advances in gene sequencing over
just the past 10 years that have made it possible to identify more microbes and
possibly even get an idea of what they’re doing.

People are much more curious and concerned (and confused) about their
gut health now. The near future is uncertain because the field is so new and
turbulent. To put it into perspective, insulin was discovered 100 years ago, in
1921, and it revolutionized the treatment of diabetes. However, early insulin-
based treatments were difficult to produce and came with many health risks.
It took a little more than 50 years before synthetic insulin was developed,
and the first artificial pancreas was only approved by the FDA within the last
10 years. Who knows how long it might take to come up with microbiome-
centered therapies? That said, technology tends to improve exponentially, so
researchers might find answers and solutions faster with each new generation.

READING
Benedict, C., H. Vogel, W. Jonas, A. Woting, M. Blaut, A. Schürmann, and J. Cedernaes.
“Gut Microbiota and Glucometabolic Alterations in Response to Recurrent Partial Sleep
Deprivation in Normal-Weight Young Individuals.” Molecular Metabolism 5, no. 12
(2016): 1175–1186. https://doi.org/10.1016/j.molmet.2016.10.003.

Manor, O., C. L. Dai, S. A. Kornilov, B. Smith, N. D. Price, J. C. Lovejoy, S. M.

Gibbons, et al. “Health and Disease Markers Correlate with Gut Microbiome
Composition across Thousands of People.” Nature Communications 11 (2020): 5206.
https://doi.org/10.1038/s41467-020-18871-1.

Mawdsley, J. E., and D. S. Rampton. “Psychological Stress in IBD: New Insights into
Pathogenic and Therapeutic Implications.” Gut 54, no. 10 (2005): 1481–1491.
https://doi.org/10.1136/gut.2005.064261.

Mikocka-Walus, A. A., V. Pittet, J. B. Rossel, R, von Känel, and the Swiss IBD Cohort
Study Group. “Symptoms of Depression and Anxiety Are Independently Associated
with Clinical Recurrence of Inflammatory Bowel Disease.” Clinical Gastroenterology and
Hepatology 14, no. 6 (2016): 829–835. https://doi.org/10.1016/j.cgh.2015.12.045.

96
 12. A Lifestyle for Gut Health

Mortaş, H., S. Bilici, and T. Karakan. “The Circadian Disruption of Night Work
Alters Gut Microbiota Consistent with Elevated Risk for Future Metabolic and
Gastrointestinal Pathology.” Chronobiology International 37, no. 7 (2020): 1067–1081.
https://doi.org/10.1080/07420528.2020.1778717.

Nunan, D., T. Cai, A. D. Gardener, J. M. Ordóñez-Mena, N. W. Roberts, E. T.

Thomas, and K. R. Mahtani. “Physical Activity for Treatment of Irritable
Bowel Syndrome.” Cochrane Database of Systematic Reviews 6, no. 6 (2022).
https://doi.org/10.1002/14651858.CD011497.pub2.

Palsson, O. S., and S. Ballou. “Hypnosis and Cognitive Behavioral Therapies for the
Management of Gastrointestinal Disorders.” Current Gastroenterology Reports, 22, no. 7
(2020): 31. https://doi.org/10.1007/s11894-020-00769-z.

Smith, R. P., C. Easson, S. M. Lyle, R. Kapoor, C. P. Donnelly, E. J. Davidson, E. Parikh,

et al. “Gut Microbiome Diversity Is Associated with Sleep Physiology in Humans.” PloS
One 14, no. 10 (2019): e0222394. https://doi.org/10.1371/journal.pone.0222394.

Sugaya, N., K. Shirotsuki, and M. Nakao. “Cognitive Behavioral Treatment for Irritable
Bowel Syndrome: A Recent Literature Review.” BioPsychoSocial Medicine 15, no. 1
(2021): 23. https://doi.org/10.1186/s13030-021-00226-x.

97
Notes
Notes
Notes
Notes
Notes
Notes
Notes
Notes
Notes