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ESSR Published Ahead-of-Print Heading: Perspectives for Progress Exercise and the gut microbiome: a review of the evidence, potential mechanisms, and implications for human health

January 2019
Exercise and Sport Sciences Reviews 47(2)

DOI:10.1249/JES.0000000000000183

Authors:

Lucy Mailing

University of Illinois, Urbana-Champaign

Jacob Allen

University of Illinois, Urbana-Champaign

Thomas W Buford

University of Alabama at Birmingham

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The gastrointestinal tract contains trillions of microbes (collectively known as the gut microbiota) that play essential roles in host physiology and health. Studies from our group and others have demonstrated that exercise independently alters the composition and functional capacity of the gut microbiota. Here, we review what is known about the gut microbiota, how it is studied, and how it is influenced by exercise training and discuss the potential mechanisms and implications for human health and disease.

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ESSR Published Ahead-of-Print

Heading: Perspectives for Progress

Accepted: 01/18/2019

Editor: Marni D. Boppart, ScD, FACSM

Exercise and the gut microbiome: a review of the evidence, potential mechanisms, and

implications for human health

Lucy J. Mailing1, Jacob M. Allen2, Thomas W. Buford3, Christopher J. Fields4, Jeffrey A.

Woods1,5

1 Division of Nutritional Sciences, University of Illinois Urbana-Champaign, IL

2 Center for Microbial Pathogenesis, Nationwide Children‘s Hospital, Columbus, OH

3 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL

4 High Performance Computing in Biology, Carver Biotechnology Center, University of Illinois

Urbana-Champaign, IL

5 Department of Kinesiology and Community Health, University of Illinois Urbana-Champaign,

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Exercise and the gut microbiome: a review of the evidence, potential

mechanisms, and implications for human health

Lucy J. Mailing1, Jacob M. Allen2, Thomas W. Buford3, Christopher J. Fields4, Jeffrey A.

Woods1,5

1 Division of Nutritional Sciences, University of Illinois Urbana-Champaign, IL, United States

2 Center for Microbial Pathogenesis, Nationwide Children‘s Hospital, Columbus, OH, United

States

3 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United

States

4 High Performance Computing in Biology, Carver Biotechnology Center, University of Illinois

Urbana-Champaign, IL, United States

5 Department of Kinesiology and Community Health, University of Illinois Urbana-Champaign,

IL, United States

Corresponding Author:

Jeffrey A. Woods, PhD

1206 South 4th Street

1008A Khan Annex, Huff Hall

University of Illinois at Urbana-Champaign

Champaign IL 61820

Woods1@illinois.edu

Exercise and Sport Sciences Reviews, Publish Ahead of Print

DOI: 10.1249/JES.0000000000000183

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Funding: The authors have no funding to disclose for the preparation of this manuscript. TB‘s

effort toward this manuscript partially supported by grants from the National Institutes of Health

(P2CHD086851 and P30AG050886).

Conflicts of interest: The authors have no conflicts of interest to report.

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ABSTRACT

The gastrointestinal tract contains trillions of microbes (collectively known as the gut

microbiota) that play essential roles in host physiology and health. Studies from our group and

others have demonstrated that exercise independently alters the composition and functional

capacity of the gut microbiota. Here, we review what is known about the gut microbiota, how it

is studied, how it is influenced by exercise training, and discuss the potential mechanisms and

implications for human health and disease.

KEYWORDS: Endurance exercise; gut microbiota; short-chain fatty acids; butyrate; gut health;

inflammatory bowel disease

KEY POINTS

 The trillions of microbes in the gut play essential roles in human health

 Exercise training alters the composition and functional capacity of the gut microbiota,

independent of diet

 Exercise-induced alterations of the gut microbiota may depend on obesity status, exercise

modality, and exercise intensity.

 Exercise-induced alterations of the gut microbiota are likely to have numerous benefits

for human health

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INTRODUCTION

Scientists have only recently begun to appreciate the human gut as a complex ecosystem of

bacteria, archaea, eukaryotes, and viruses that have co-evolved with humans over thousands of

years. Known collectively as the gut microbiota, these microbes can weigh up to two kilograms

and are imperative to host digestion, metabolic function, and resistance to infection (1). The

human gut microbiota has an enormous metabolic capacity, with over 1000 different unique

bacterial species and over 3 million unique genes (2). Collectively, the sum of the microbial

genes in the gut is called the gut microbiome.

Given the numerous roles of the gut microbiota in host physiology and pathophysiology, it‘s not

surprising that there is great interest in identifying ways to manipulate microbial communities in

health and disease (3–5). While diet is well known to modulate the composition of the gut

microbiota, recent studies suggest that exercise can alter gut microbial communities as well. This

will be the focus of the present review. Key questions include: Does exercise independently alter

the gut microbiota? If yes, by what mechanism? With what implications for the gut and other

organ systems? Can exercise beneficially modulate the gut microbiota in states of disease?

Before we attempt to answer these questions, we will first review advances in technology that

have improved the understanding of the microbiota‘s contribution to health and disease and

enabled investigations into exercise‘s impact on gut microbial communities.

BASIC MICROBIOME METHODOLOGY

Until the 1990s, scientific study of gut microbes primarily relied on culture, staining, and

microscopy (6). Growth media and conditions typically favored fast-growing, aerobic microbes,

meaning that many anaerobic microbes could not be effectively cultured or studied (7). This

changed with the advent of DNA sequencing. 16S bacterial ribosomal RNA (rRNA) gene

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sequencing (hereafter 16S) quickly became the most popular (8). The conserved regions of this

gene are used to design broad-spectrum PCR primers that allow for the amplification of the more

rapidly-evolving hypervariable regions across a broad spectrum of microbes (Figure 1). The

resulting amplified hypervariable region sequences can then be classified taxonomically by

comparing them to a curated database of fully sequenced bacterial 16S genes (9).

16S is still the most widely used method to cost-effectively characterize bacterial communities in

a research setting (10), but it does have several limitations. First, taxonomic classifications are

limited primarily to bacteria. Second, sequence classification is normally limited to the genus

level, as multiple species may have the same sequence within the studied hypervariable region

(11). 16S is also susceptible to primer bias (12,13). Finally, 16S analysis does not provide direct

information about the function of gut microbes or the potential interactions with host physiology,

though tools such as PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of

Unobserved States) can infer potential functional pathways from 16S results utilizing

information from the Human Microbiome Project (14).

TARGETED GENOMICS, META-OMICS, AND METABOLITES

Recently, interest has increased for moving beyond 16S (‗who‘s there?‘) to better understand the

role of the gut microbiota in states of health and disease (‗what are they doing?‘). One way to do

this involves using specific degenerate primers to perform quantitative PCR (qPCR) for a

specific conserved microbial gene. For example, our lab has targeted the butyryl-CoA:acetate-

CoA transferase (BCoAT) gene, which encodes the primary enzyme involved in gut bacterial

production of the short-chain fatty acid (SCFA) butyrate (15). This targeted genomics approach

is relatively quick and inexpensive but limited in overall scope.

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In contrast, metagenomics (i.e. shotgun sequencing) involves assessing the entire gene content of

a given microbial community (16) to assess microbial functions and allow for identification of

bacteria, archaea, viruses, and fungi with greater specificity (2,17). Current limitations for

metagenomics include high cost, sequencing biases, complexity in both data processing and

analysis, and incomplete databases for taxonomy and genomic assignment (16). Nevertheless,

newer sequencing technologies as well as upgraded downstream pipelines (18,19) and reference

databases (20,21) have greatly improved taxonomic and functional genomic profiling of the gut

microbiota. Other meta-omics, such as meta-transcriptomics, -proteomics, and -metabolomics

can help elucidate which genes are actually expressed and become functional proteins capable of

carrying out diverse metabolic functions (22). These high-throughput, high-resolution techniques

are rapidly improving in speed, quality, and cost, and will soon be the norm for microbiome

research.

Metabolites can also be measured directly using gas or liquid chromatography and mass

spectrometry to provide insight into the collective metabolic function of the gut. However,

quantitation of certain volatile metabolites requires prompt collection and acidification or ethanol

treatment of samples after collection (23). Moreover, the fecal concentration of many gut

metabolites will depend on gut transit time, cross-feeding interactions between microbes, and

rate of host absorption (24), so it is not necessarily representative of luminal concentrations.

STATISTICAL INTERPRETATION OF GUT MICROBIOME DATA

Microbiome data analysis is typically performed using an open-source bioinformatics pipeline,

such as Quantitative Insights Into Microbial Ecology 2 (QIIME 2) (25) or Mothur (26) for 16S

and Metagenomics Reports (METAREP) (27), Metagenome Analyzer (MEGAN) (28), or

Metagenomic Rapid Annotations using Subsystems Technology (MG-RAST) (29) for

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comparative metagenomics. For 16S, sequences from samples must be de-multiplexed, quality

filtered, and clustered into operational taxonomic units (OTUs) based on sequence identity (ID)

(i.e. about 95% ID for genus; 97% ID for species). These are then taxonomically classified using

common reference databases (30,31) and visualized as a phylogenetic tree or represented using

bar plots.

The alpha ()-diversity metrics Chao1, Shannon index, and Simpson index are a measure of the

diversity within a sample and take into account both the number of unique OTUs in a sample

(richness) and the relative abundance of these OTUs (evenness). In contrast, beta ()-diversity

metrics like Bray-Curtis and UniFrac are measures of the diversity between samples. When more

than two samples are used, -diversity is calculated for every pair of samples to create a distance

(dissimilarity) matrix. The data present in the -diversity distance matrix can be visualized using

a 2-D or 3-D Principle Coordinates Analysis (PCoA) plot, where each axis explains a certain

percentage of variation present in the dataset. Each sample is represented by a single point, and

the distance between points reflects how compositionally different the samples are from one

another (32). Statistical significance of community-level differences can be assessed using a

PERMANOVA test (33).

FACTORS INFLUENCING THE GUT MICROBIOME

Using these methodologies, several factors have been identified that influence gut microbial

composition and metabolic capacity beginning at birth. The fetal gut contains few if any

microbes as the womb is largely sterile (34). Microbial colonization begins at birth and is

significantly influenced by mode of delivery (vaginal or Cesarean section) and infant diet

(breastmilk or formula) (35). Other factors, including increased sanitation, reduced exposure to

infection through vaccination, elimination of entero-pathogens, and exposure to antibiotics and

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non-antibiotic drugs can also alter the commensal, or native, microbiota (36). Dietary intake also

has a significant impact on microbial composition throughout life (37).

EXERCISE AND THE GUT MICROBIOME: EVIDENCE IN ANIMAL STUDIES

Emerging research from our group and others suggests that exercise also influences the gut

microbiota. Over a dozen controlled animal studies have shown that exercise training

independently alters the composition and functional capacity of the gut microbiota (38–51).

Matsumoto et al. (2008) was the first to find that five weeks of exercise training resulted in an

increase in the bacterial metabolite butyrate. Several other studies have recapitulated this finding

and shown that exercise training increases the relative abundance of butyrate-producing taxa

(38,41). Butyrate is a short-chain fatty acid (SCFA) produced from the bacterial fermentation of

dietary fiber. As the primary fuel for colonocytes, butyrate has been shown to increase colonic

epithelial cell proliferation, promote gut barrier integrity, and regulate the host immune system

and gene expression (52,53).

Drawing other broad conclusions as to how and to what degree exercise alters the rodent gut

microbiota has proved difficult due to incongruities in diet, species/strain, animal age, and

exercise modality used. For instance, several studies suggest that exercise increases the ratio of

Firmicutes to Bacteroidetes phyla (38–40), while some studies suggest that exercise reduces this

ratio (41–44). Still others have found no change at the phylum level (45,46). Several factors may

influence the disparate results observed in these studies. For instance, we recently reported that

voluntary wheel running (VWR) and forced treadmill running (FTR) – the two most common

modes of endurance exercise used with rodents – differentially altered the gut microbiota (47).

Mika et al. (2015) found that microbial genera were more robustly altered by VWR in juvenile,

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as compared to the adult rats (44), while Evans et al. (2014) found that VWR increased microbial

diversity, but only in mice fed a high-fat diet (41).

EXERCISE AND THE GUT MICROBIOME: HUMAN CROSS-SECTIONAL

EVIDENCE

Evidence for a role of exercise in shaping the human gut microbiota first emerged from cross-

sectional studies (Table 1). Clarke et al. (2014) found that the gut microbiota of professional

rugby players had greater alpha diversity and a higher relative abundance of 40 different

bacterial taxa than the gut microbiota of lean sedentary controls. The athletes also had lower

abundance of Bacteroides and Lactobacillus species (spp.) than their lean sedentary counterparts

(54). More recently, Bressa et al. (2017) compared active women to sedentary controls (55) and

observed that women who performed at least three hours of exercise per week had increased

levels of Faecalibacterium prausnitzii, Roseburia hominis, and Akkermansia muciniphila. F.

prausnitzii and R. hominis are known butyrate producers (56), while A. muciniphila has been

associated with a lean BMI and improved metabolic health (57).

Several studies have also attempted to correlate the composition and metabolic capacity of the

microbiota with cardiorespiratory fitness. Durk et al. (2018) showed that a higher ratio of

Firmicutes to Bacteroidetes, the two predominant phyla in the human gut microbiota, was

significantly correlated with maximal oxygen uptake (VO2 max) (58). Estaki et al. (2016) found

that in younger adults, microbial diversity and abundance of butyrate-producing bacterial taxa

were positively correlated with cardiorespiratory fitness (59), while Barton et al. (2017) showed,

using metagenomic analyses, that athletes have altered gut microbial pathways for amino acid

biosynthesis and carbohydrate metabolism and greater fecal SCFA concentrations (60).

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Nevertheless, all of these studies were limited by their cross-sectional design and their inability

to control for the effects of diet (and perhaps other factors) on the gut microbiota. There is

considerable inter-individual variability in the composition of the microbiota, and active

individuals tend to eat differently from sedentary individuals. For instance, Clarke et al. (2014)

found that increased protein intake by elite rugby players accounted for many of the observed

differences in the gut microbiota (54). These limitations suggested the need for longitudinal

studies to determine whether exercise independently alters the gut microbiota in humans.

EXERCISE AND THE GUT MICROBIOME: HUMAN LONGITUDINAL STUDIES

Recently, members of our group published findings from the first controlled longitudinal study to

assess the effects of exercise on the gut microbiome (61). In total, 32 sedentary adults (lean [BMI

<25] or obese [BMI>30]) participated in a six-week supervised endurance exercise program (30-

60 minutes duration, 3x/week) with stringent dietary controls. Several taxa were differentially

altered by exercise depending on BMI status. For instance, exercise increased Faecalibacterium

spp. in lean subjects, but reduced its abundance in obese subjects; Bacteroides spp. decreased in

the lean subjects and increased in the obese subjects. Six weeks of exercise also increased the

abundance of butyrate-producing taxa and fecal acetate and butyrate concentrations, but only in

lean subjects. Interestingly, most bacterial taxa and SCFAs that increased with exercise

subsequently decreased during the six-week sedentary washout period that followed, indicating

that the effects of exercise on the microbiota were both transient and reversible.

Similarly, Cronin et al. (2018) sought to determine whether a short-term exercise regime, with or

without whey protein supplementation, could alter gut microbial composition and function in

predominantly overweight or obese male and female adults (n=90) (62). Those randomized to the

exercise groups were required to perform moderate intensity aerobic training (18-32 minutes

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duration) and a progressive resistance training program three times per week for eight weeks.

Post-intervention assessment did not reveal any significant changes in taxonomic composition or

metabolic pathways in either exercise group compared to baseline. However, a trend was seen

for an increase in bacterial diversity in the exercise and exercise + whey protein groups,

compared to the group that received whey protein alone. Metagenomic and metabolomic

analyses revealed only modest alterations of microbial metabolism. While the study had a fairly

large sample size, the authors note that self-reported maintenance of usual dietary intake and a

wide BMI range may have prevented detection of more significant changes.

Munukka et al. (2018) performed a similar study to determine whether endurance exercise could

affect the gut metagenome in previously sedentary overweight women (n=17) (63). Six-weeks of

light to moderate intensity cycling resulted in an increased relative abundance of Akkermansia

muciniphila and a decrease in Proteobacteria. Most interestingly, only about half of the subjects‘

microbiomes responded considerably to exercise. Metagenomic analysis revealed that exercise

training decreased the abundance of several genes related to fructose and amino acid metabolism.

Together, these findings suggest that exercise has independent effects on the gut microbiota, but

longer duration or higher intensity aerobic training may be required to induce significant

taxonomic and metagenomic changes. Furthermore, the microbiota of lean individuals may be

more responsive to an exercise intervention than that of overweight or obese individuals.

POTENTIAL MECHANISMS

There are several potential mechanisms by which exercise might alter the gut microbiota (Figure

2). The gut-associated lymphoid tissue, or GALT, lies through the small and large intestine and

contains about 70 percent of the body‘s immune cells. Several animal studies performed by

Hoffman-Goetz et al. have found that exercise alters the gene expression of intraepithelial

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lymphocytes, downregulating pro-inflammatory cytokines and upregulating anti-inflammatory

cytokines and antioxidant enzymes (64–66). These immune cells reside in close proximity to

microbial communities and produce antimicrobial factors that are essential for mediating host-

microbial homeostasis (67). Similarly, exercise may impact the integrity of the gut mucus layer,

which plays important role in keeping microbes from adhering to the gut epithelium and serves

as an important substrate for certain mucosa-associated bacteria, such as Akkermansia

muciniphila.

Exercise raises core temperature and results in heat stress, particularly when performed for long

durations or in a hot environment (68). Exercise can also reduce intestinal blood flow by more

than 50 percent, with significant gut ischemia occurring within 10 minutes of high-intensity

exercise (69). Upon rest, the splanchnic bed undergoes rapid reperfusion. While the intestine is

an anaerobic environment, gut epithelial cells primarily utilize oxidative metabolism, and high-

intensity exercise is known to transiently impair gut barrier function (69,70). Thus, exercise-

induced heat stress and ischemia may briefly result in more direct contact between the gut

mucosal immune system and the microbes that reside in the gut lumen and mucosa, with

potential consequences for gut microbial communities.

While intestinal permeability occurs briefly during acute exercise, contact between microbes and

the immune system may be reduced at rest with regular physical activity. Trained athletes have

lower levels of circulating bacterial endotoxin lipopolysaccharide (LPS) at rest than sedentary

individuals (71), and a greater heat shock protein response to heat stress (72). Increased heat

shock proteins in the gut have been shown to prevent breakdown of tight junction proteins

between epithelial cells (73). Thus, it‘s plausible that exercise represents a hormetic stressor to

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the gut that stimulates beneficial adaptations and improves the long-term resilience of the gut

barrier.

Altered gut motility and/or activity of the enteric nervous system is another mechanism by which

exercise may influence the gut microbiome. Exercise reduces transit time in the large intestine

and has been shown to accelerate the movement of gas through the gastrointestinal (GI) tract

(74,75). Exercise is also well known to impact the autonomic nervous system increasing vagal

and overall sympathetic tone (76), but it‘s impact on the complex mesh-like network of neurons

that innervate the gut has not been well elucidated. Nonetheless, regional or global changes in GI

transit are likely to have profound effects on intestinal pH, mucus secretion, biofilm formation,

and availability of nutrients to microbes. Mechanical forces are also increased in the abdomen

during most forms of aerobic exercise, which could potentially influence gut motility or increase

the mixing of intestinal contents.

Exercise training may also alter the entero-hepatic circulation of bile acids. Meissner et al.

(2011) found that hypercholesterolemic mice that were given access to a running wheel for 12

weeks displayed increased bile acid secretion and increased fecal bile acid outputs compared to

hypercholesterolemic mice that remained sedentary (77). Bile acids are potent regulators of gut

microbiota community structure, and an absence of these molecules is associated with significant

alterations in gut microbial communities (i.e. gut dysbiosis) (78). Thus, changes in the bile acid

pool could significantly shift the gut microbiome with exercise.

Lastly, exercise significantly alters metabolic flux (the rate of turnover of molecules through

metabolic pathways) and requires contraction of skeletal muscle, which stimulates the release of

myokines, metabolites, and neuroendocrine hormones that may interact with the gut directly or

indirectly through a common interface with the immune system (79). Significant amounts of

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lactate are released into the blood during exercise, which could alter intestinal pH if any of this

lactate is secreted into the gut lumen. Overall, more research is needed to determine which of

these mechanisms are responsible for the adaptation of the gut microbiota to exercise training.

IMPLICATIONS FOR THE GUT AND BEYOND

Exercise-induced alterations of the gut microbiota likely have implications for gut and whole-

body health. Physical activity has been shown to be protective against many chronic diseases and

offers an attractive and cost-effective way to improve quality of life (80). Though under-

recognized to date, many of these benefits may be derived via interactions with the gut

microbiota (Figure 3). Here, we discuss potential example conditions for which the gut

microbiota may play a pivotal role, though they almost certainly do not represent the full

spectrum of potential benefits. It should also be noted that in most cases the potential attribution

of beneficial effects to the gut microbiota remains speculative due to the lack of definitive data in

this area.

Colorectal cancer

Observational studies indicate that physically active individuals have a 24% reduced risk for

colorectal cancer compared to sedentary individuals (23). Beginning an exercise program after

the onset of colorectal cancer may also improve quality of life and reduce overall mortality (82).

In preclinical animal studies, VWR has been shown to reduce colon tumor incidence (83). One

mechanism for this may be increased butyrate production from exercise. Colorectal cancer

patients have been shown to have an altered gut microbiota characterized by a reduced

abundance of butyrate-producing taxa, including Roseburia and Lachnospiraceae (84).

In vitro studies have shown that butyrate differentially regulates gene expression in healthy and

cancerous cells (85). In healthy epithelial cells, butyrate is rapidly metabolized via the

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mitochondrial tricarboxylic acid (TCA) cycle. This results in a buildup of cytosolic citrate and

acetyl CoA and increases the acetylation of histones by histone acetyltransferases (HATs). This

epigenetic modification increases expression of genes involved in cell proliferation and cell

turnover, effectively strengthening the intestinal barrier (85).

In colorectal cancer cells, however, mitochondrial dysfunction results in an accumulation of

butyrate in the cytosol. Free butyrate inhibits histone deacetylases (HDACs), which results in the

epigenetic suppression of proliferation and promotion of cell death pathways (85). This may

ultimately lead to a reduction in tumor size and reduces the chance of metastasis. Indeed,

Basterfield & Mathers et al. (2010) found that Min mice, which are genetically predisposed to

intestinal adenomas, had a reduced number of large tumors in the colon and a trend towards

reduced tumor multiplicity with exercise training. There was a weak correlation between fecal

butyrate concentrations and tumor number (86).

Inflammatory bowel disease

Inflammatory bowel disease (IBD) includes both Crohn‘s disease and ulcerative colitis (UC) and

is characterized by inappropriate gut immune responses and an altered microbiota. IBD patients

have an increased relative abundance of Enterobacteriaceae and reduced abundance of

Roseburia, a genus known to produce butyrate and induce regulatory T cell formation (87).

Regulatory T cells are important for modulating the immune system, promoting tolerance to self-

antigens, preventing autoimmune disease, and dampening inflammation. Metagenomic analysis

also revealed reduced carbohydrate metabolism and amino acid biosynthesis in the fecal

microbiome of IBD patients compared to healthy controls (87) – two pathways that exercise has

been reported to increase. Indeed, higher self-reported physical activity levels are associated with

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a 22 percent reduced risk of active UC (88), and a ten week intervention that included moderate

exercise improved quality of life in patients with moderately active UC (89).

Our group and others have performed several preclinical animal studies on the effects of exercise

on colitis. Szalai et al. (2014) found that six weeks of VWR increased expression of heme

oxygenase and nitric oxide synthase, increased anti-inflammatory cytokines, and reduced

inflammatory markers and the severity of mucosal damage in TNBS-induced colitis (90), while

Liu et al. (2015) found that one month of VWR suppresses pro-inflammatory cytokine

production in response to dextran sodium sulfate (DSS)-induced colitis by up-regulating

glucocorticoid-mediated peroxisome proliferator-activated receptor gamma (PPAR‐γ)

expression in the colon (91). PPAR‐γ regulates fatty acid storage and glucose metabolism. In

2013, members of our group confirmed that VWR conferred protection against DSS-induced

colitis and reduced disease-related symptoms and mortality, but additionally observed that FTR

exacerbated symptoms and led to higher mortality (92). Further study revealed that VWR and

FTR resulted in distinct changes in the gut microbiota (47).

To determine if exercise-induced alterations in the gut microbiota were directly responsible for

the protective effects of VWR, members of our group transferred cecal contents from exercised

or sedentary mice into naïve, sedentary germ-free mice in the first-ever ―exercise‖ fecal

microbiota transplant (FMT). When recipient mice were later subjected to an acute colitis insult

with DSS, those that had received a microbiota from exercised mice lost significantly less body

weight and had fewer clinical symptoms than those that received a microbiota from sedentary

mice. Mice receiving the microbiota from exercised mice also had a more regenerative cytokine

profile, with significantly higher levels of transforming growth factor beta (TGF-β), forkhead

box P3 (FoxP3), and interleukin (IL-22) gene expression in the distal colon (93). More studies

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are needed to determine whether exercise can beneficially modulate the gut microbiota in

humans with IBD, and whether compositional alterations parallel improvements in

symptomology.

Obesity and metabolic disease

Several studies have shown that the gut microbiota is closely associated with obesity and

metabolic syndrome. A seminal paper by Turnbaugh et al. (2006) showed that transplanting fecal

material from an obese mouse into a germ-free mouse resulted in rapid weight gain (94). The

obese microbiota has a significantly higher capacity for energy harvest from the diet and may

also promote intestinal permeability, allowing the influx of endotoxin into the bloodstream.

Endotoxemia itself has been shown to result in weight gain and insulin resistance (95).

Evidence from animal studies suggests that exercise may attenuate the gut dysbiosis and altered

intestinal villi morphology induced from high-fat diet feeding (45). Queipo-Ortuño et al. (2013)

found that just six days of VWR increased the relative abundance of Lactobacillus and

Bifidobacterium spp. in male rats, which were positively correlated with serum leptin levels (42),

while Lambert et al. (2015) found significant interactions between exercise and diabetic state on

the gut microbiota in an animal model of type 2 diabetes (40).

Lai et al. (2018) showed that high-fat diet fed obese mice receiving FMT from exercised,

normal-fat diet fed donor mice showed improvements in metabolic parameters, including weight

loss, reduced fasting blood glucose, and lower hepatic expression of pro-inflammatory cytokines

(96). Notably, two of the taxa that were highly associated with FMT from exercised donors,

Odoribacter and AF12 of the family Rikenellaceae, are known butyrate-producers. In animal

models of obesity, butyrate has been shown to increase energy expenditure, improve insulin

sensitivity, and reduce adiposity (97). Butyrate and other SCFAs also stimulate the production of

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satiety hormones, which help regulate food intake, and may help delay or attenuate the

development of diabetes by improving gut barrier function (98).

Mental and cognitive health

The gut microbiota has also been implicated in mental health and cognition, and the existence of

a gut-brain axis is well established (99,100). Gut microbiota-derived metabolites have been

shown to activate receptors on vagal afferents of the enteric nervous system, and certain

microbes are also capable of producing neurotransmitters; for example, Lactobacillus spp. can

produce both serotonin and gamma-aminobutyric acid (GABA) (101). Serotonin is thought to

play a role in emotion and cognitive functions, and low levels have been linked to depression.

GABA is the chief inhibitory neurotransmitter in the central nervous system and typically has

anti-anxiety and relaxant effects. Thus, it‘s no surprise that germ-free mice that lack a

commensal microbiota exhibit altered brain function, abnormal behaviors, and an exaggerated

hypothalamic-pituitary-adrenal response to stress (102).

Gut dysbiosis may also contribute to impaired mental health. Human patients with major

depressive disorder have an altered gut microbiota, characterized by changes in the relative

abundance of Firmicutes, Bacteroidetes, and Actinobacteria (103). Notably, transferring fecal

material from these patients into germ-free mice confers depression-like behaviors in the

recipient mice (103). Stevens et al. (2017) found that patients with a depressive or anxiety

disorder had a unique predicted gut metagenomic profile and increased levels of plasma markers

of intestinal permeability (104).

Exercise is well-known to have benefits for mental and neurological health (105), and it is

plausible that some of the beneficial effects of exercise on the brain are mediated by the gut

microbiota. For instance, Kang et al. (2014) found that an hour of daily wheel running increased

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the relative abundance of Lachnospiraceae, a family of known butyrate-producing microbes,

which was negatively correlated with anxiety-like behavior in adult C57Bl/6J mice (38).

Butyrate itself has been shown to upregulate brain-derived neurotrophic factor (BDNF)

expression in the hippocampus and frontal cortex of mice, which helps to support the survival of

existing neurons and encourage the formation of new neurons and synapses. Butyrate has also

been shown to regulate the activation of microglial cells, a specialized population of immune

cells in the brain (106,107). Like exercise, butyrate also appears to increase neuroplasticity and

has anti-depressant activity, boosting brain serotonin levels (108).

FUTURE PERSPECTIVES

Overall, increasing evidence suggests that regular aerobic exercise confers benefits to the gut

microbiota, which may be partially responsible for the widespread benefits of regular physical

activity on human health. This area of research will no doubt have many exciting developments

in the coming decade, and there are many questions that are yet be answered (Figure 2). In

addition to elucidating the mechanisms involved, the effects of different forms of exercise

necessitates further study. Open questions include: ―What frequency, mode, or intensity of

exercise is best? How does exercise impact the gut microbiome in children or the elderly? In

healthy or diseased states? How does exercise interact with diet in shaping the gut microbiome?

Do probiotics or prebiotics influence gut responses to an exercise intervention? What about

resistance exercise?‖

Future research should also employ methodologies to elucidate the effects of exercise on the

microbiome in various regions of the GI tract, including microbes associated with the gut mucus

layer. While this will likely involve more invasive endoscopic procedures for human studies, it is

critical to understand the true dynamics of the gut environment. A recent study by Zmora et al.

ACCEPTED

(2018) suggests that fecal samples often under- or over-represent the relative abundance of

various bacterial genera and species in the human gut (109).

While we have learned a great deal about how exercise influences bacterial communities, future

research should also seek to understand how exercise influences archaea, fungi, and viruses in

the human gut, and how exercise influences gut competition and ecological patterns. The

increasing feasibility of metagenomic studies will also help to elucidate which bioactive

metabolites produced by the gut microbiota might be most affected by exercise training.

Gnotobiotic, or germ-free, animal studies will also help to determine how exercise-induced

alterations in the gut microbiota are causally linked to alterations in disease risk. Ultimately, we

can imagine a future of personalized microbiome-based lifestyle medicine, where baseline gut

microbiota, diet, and other host factors might help predict which exercise program might be most

effective for a given individual.

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ACKNOWLEDGEMENTS

TB‘s effort toward this manuscript partially supported by grants from the National Institutes of

Health (P2CHD086851 and P30AG050886).

Funding: The authors have no funding to disclose for the preparation of this manuscript.

Conflicts of interest: The authors have no conflicts of interest to report.

ACCEPTED

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8674(18)31102-4

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FIGURE LEGENDS

Figure 1. Methodologies commonly used to study the gut microbiome. Fecal or GI content

samples can be used for metabolite analysis or undergo chemical and mechanical digestion to

extract nucleic acids. Extracted DNA can be used for targeted genomics, shotgun sequencing, or

16S rRNA gene amplification.

Figure 2. Current unknowns and future areas of research related to exercise and the gut

microbiome. While several studies have now shown that exercise alters gut microbiota

composition, functional capacity, and metabolites, the effects of different exercise frequencies,

modes, and intensities is unknown. Assessing the effects of exercise on the gut microbiota in

different populations and its synergy with different diets also represents a key area of future

research. Mechanistic studies, such as those that utilize mice, will help determine the potential

mechanisms involved, and whether exercise-induced changes in the gut environment are

potentially disease modifying.

Figure 3. Proposed model for how exercise alters the gut microbiota and gut epithelium

with potential implications for human health. Exercise has been shown to increase butyrate-

producing taxa and fecal butyrate concentrations and reduce pro-inflammatory cytokines and

oxidative stress in the gut. Exercise is also known to have benefits on whole-body physiology,

and is protective against colon cancer, inflammatory bowel disease, depression, anxiety, and

obesity. Whether this disease protection is mediated by exercise-induced changes in the gut

microbiome and gut epithelium remains to be determined.

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Figure 1

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Figure 2

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Figure 3

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Table. Summary of cross-sectional and longitudinal studies assessing the impact of physical activity status or an exercise intervention

on the human gut microbiome.

STUDY

DESIGN

SUBJECTS

EXERCISE

TRAINING

CHANGE OR

CONTROL OF

DIET

IMPACT ON GUT MICROBIAL

COMMUNITIES

Clarke et al,

2014

Cross-

sectional

Elite rugby players

(n=40), low BMI

controls (n=23), and

high BMI controls

(n=23)

n/a

Elite athletes

consumed significantly

more protein and total

energy. Increased

protein intake

accounted for many

observed differences in

gut microbial

composition.

Greater alpha diversity in elite

athletes compared to lean sedentary

controls. ↑Akkermansia in athletes

and low BMI controls;

↑Erysipelotrichaceae, S24-7,

Prevotella and Succinivibrio and

↓Lactobacillaceae, Bacteroides, and

Lactobacillus spp. in athletes

compared to lean controls

Estaki et al.

2016

Cross-

sectional

Healthy adults with

varying

cardiorespiratory

fitness levels (n=39)

n/a

Protein intake was

highly associated with

overall microbial

community

composition.

VO2 peak accounted for more than

20 percent of the variation in species

richness. Individuals with higher

fitness had increased relative

abundance of butyrate-producing

taxa and increased fecal butyrate

concentrations.

Stewart et

al. 2016

Cross-

sectional

Adult males Type 1

diabetics with good

glycemic control and

high levels of physical

n/a

Not assessed.

Gut microbial composition of

patients with Type 1 diabetes in

good glycemic control and with high

physical fitness levels is comparable

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fitness (n=10) and

matched healthy adult

male controls (n=10)

to those of matche people without

diabetes

Bressa et al.

2017

Cross-

sectional

Premenopausal

women, active (>3

hours of physical

exercise/wk, n=19) or

sedentary (<30

minutes 3 days/wk,

n=21)

n/a

Greater consumption

of fruits and

vegetables by active

group; sedentary group

ingested more

processed meats.

Increased relative abundance of

Faecalibacterium prausnitzii,

Roseburia hominis, and Akkermansia

muciniphila in active women;

reduced relative abundance of

Barnesiellaceae, Odoribacteraceae

Yang et al.

2017

Cross-

sectional

Premenopausal

women, all activity

levels, primarily

overweight or obese

(n=71)

n/a

No significant

differences between

groups in

macronutrient

composition, fiber, or

total energy intake.

Lower VO2 max was associated with

lower relative abundance of

Bacteroides spp. and higher rel.

abundance of Eubacterium rectale-

Clostridium coccoides group

Barton et al.

2018

Cross-

sectional

Professional rugby

players (n=40) and

sedentary controls

with low BMI (n=22)

or high BMI (n=24)

n/a

Rugby players

consumed significantly

more protein and total

energy.

Rugby players had increased amino

acid and antibiotic biosynthesis,

carbohydrate metabolism, and

increased fecal SCFAs compared to

controls

Durk et al.

2018

Cross-

sectional

Healthy young adults

(n=20 males, n=17

females) with varying

n/a

No association

between macronutrient

intake and Firmicutes

Higher ratio of Firmicutes to

Bacteroidetes was significantly

correlated with VO2 max. VO2 max

ACCEPTED

cardiorespiratory

fitness level

to Bacteroidetes ratio.

accounted for 22 percent of the

variance in gut microbiota

composition.

Paulsen et

al. 2017

Longitudinal

Post-primary

treatment breast

cancer survivors

(n=12)

Received written

materials regarding

benefits of physical

activity. Fitness

measured at baseline

and 3 months

No significant changes

in self-reported

carbohydrate or fiber

intake. Other

macronutrients not

reported or controlled

for.

Significant association between

cardiorespiratory fitness and beta

diversity at 3 month timepoint.

Allen et al.

2018

Longitudinal

Previously sedentary

lean or obese adults

(n=32)

6 week progressive

aerobic exercise

intervention

(moderate-high

intensity) + 6 week

sedentary washout

period

Diet stability

confirmed using 7-day

diet diaries and a 3-

day control diet prior

to each fecal

collection.

Several taxa were differentially

altered depending on BMI status:

Faecalibacterium increased in lean

subjects but decreased in obese;

Bacteroides decreased in lean

subjects but increased in obese.

Increased butyrate-producing taxa,

fecal acetate and butyrate

concentrations. Effects were

reversed upon return to sedentary

lifestyle.

Cronin et al.

2018

Longitudinal

Predominantly

overweight or obese

adults randomized to

exercise-only (E),

8 week mixed

progressive moderate

aerobic exercise (18-

32 min) and

Self-reported

maintenance of dietary

intake

No significant changes in taxonomic

composition; trend for increase in

bacterial diversity in E and EP

groups. Only modest alterations of

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exercise + whey

protein (EP) or whey

protein only (P)

groups (n=30 each

group)

resistance training

(3x/week)

microbial metabolic potential.

Munukka et

al. 2018

Longitudinal

Previously sedentary,

overweight women

(n=17)

6 week cycling

exercise (low-

moderate intensity)

Diet stability

confirmed in 14

subjects using 3-day

food record; only

slight increase in

energy derived from

starch.

Increased relative abundance of

Akkermansia and decreased relative

abundance of Proteobacteria. Only

half of the subjects' microbiomes

responded to exercise. Exercise

training decreased abundance of

fructose and amino acid metabolism

related genes

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Fucoidan from Undaria pinnatifida Enhances Exercise Performance and Increases the Abundance of Beneficial Gut Bacteria in Mice

Article

Full-text available

Oct 2024
MAR DRUGS

Fucoidans, known for their diverse biological properties such as anti-inflammatory, antiviral, antitumor, and immune stimulatory effects, have recently gained attention for their potential benefits in exercise endurance, muscle mass, and anti-fatigue. However, the mechanisms by which fucoidans enhance exercise performance are still unclear. To investigate these effects, we administered 400 mg/kg/day of fucoidan extract derived from Undaria pinnatifida to 64 C57BL/6J mice over 10 weeks. We evaluated changes in running activity, mitochondrial-related gene expression in skeletal muscle, and alterations in the intestinal microbiome. Our results showed that fucoidan supplementation significantly increased daily running distance and muscle mass by 25.5% and 10.4%, respectively, in mice on a standard chow diet, and with more modest effects observed in those on a high-fat diet (HFD). Additionally, fucoidan supplementation led to a significant increase in beneficial gut bacteria, including Bacteroides/Prevotella, Akkermansia muciniphila, and Lactobacillus, along with a notable reduction in the Firmicutes/Bacteroidetes ratio, indicating improved gut microbiome health. Mechanistically, fucoidan supplementation upregulated the mRNA expression of key genes related to mitochondrial biogenesis and oxidative capacity, such as COX4, MYH1, PGC-1α, PPAR-γ, and IGF1, in both standard chow and HFD-fed mice. Our findings suggest that fucoidan supplementation enhances exercise performance, improves muscle function, and positively modulates the gut microbiome in mice, regardless of diet. These effects may be attributed to fucoidans’ potential prebiotic role, promoting the abundance of beneficial gut bacteria and contributing to enhanced exercise performance, increased muscle strength, and improved recovery.

Dietary legumes and gut microbiome: a comprehensive review

Article

Nov 2024
CRIT REV FOOD SCI

The gut microbiome plays a crucial role in human health, affecting metabolic, immune, and cognitive functions. While the impact of various dietary components on the microbiome is well-studied, the effect of legumes remains less explored. This review examines the influence of legume consumption on gut microbiome composition, diversity, and metabolite production, based on 10 human and 21 animal studies. Human studies showed mixed results, with some showing increased microbial diversity and others finding no significant changes. However, legume consumption was linked to increases in beneficial bacteria like Bifidobacterium and Faecalibacterium. Animal studies generally indicated enhanced microbial diversity and composition changes, though these varied by legume type and the host’s health. Some studies highlighted legume-induced shifts in bacteria associated with better metabolic health. Overall, the review emphasizes the complexity of legume-microbiome interactions and the need for standardized methodologies and longitudinal studies. While legumes have the potential to positively affect the gut microbiome, the effects are nuanced and depend on context. Future research should investigate the long-term impacts of legume consumption on microbiome stability and its broader health implications, particularly for disease prevention and dietary strategies.

The Gut–Heart Axis: Molecular Perspectives and Implications for Myocardial Infarction

Article

Full-text available

Nov 2024
INT J MOL SCI

Myocardial infarction (MI) remains the leading cause of death globally, imposing a significant burden on healthcare systems and patients. The gut-heart axis, a bidirectional network connecting gut health to cardiovascular outcomes, has recently emerged as a critical factor in MI pathophysiology. Disruptions in this axis, including gut dysbiosis and compromised intestinal barrier integrity, lead to systemic inflammation driven by gut-derived metabolites like lipopolysaccharides (LPSs) and trimethylamine N-oxide (TMAO), both of which exacerbate MI progression. In contrast, metabolites such as short-chain fatty acids (SCFAs) from a balanced microbiota exhibit protective effects against cardiac damage. This review examines the molecular mediators of the gut-heart axis, considering the role of factors like sex-specific hormones, aging, diet, physical activity, and alcohol consumption on gut health and MI outcomes. Additionally, we highlight therapeutic approaches, including dietary interventions, personalized probiotics, and exercise regimens. Addressing the gut-heart axis holds promise for reducing MI risk and improving recovery, positioning it as a novel target in cardiovascular therapy.

Fibrolytic efficiency of the large intestine microbiota may benefit running speed in French trotters: A pilot study

Article

Full-text available

Nov 2024

This pilot study sought to explore the contribution of the large intestine microbiota to energy metabolism and exercise performance through its ability to degrade fibers into short‐chain fatty acids (SCFAs). To investigate this, a correlational study was carried out on athlete horses under the same management conditions. Fecal microbiota diversity and composition, fibrolytic efficiency and SCFAs were analyzed. An incremental running test was carried out to estimate the maximal running speed (MRS) of the horses, and blood samples were taken to measure energy metabolism parameters. MRS was positively correlated with the efficiency of the fecal microbiota in degrading cellulose in vitro (r = 0.51; p = 0.02). The abundance of fibrolytic bacterial taxa was not associated with MRS, but functional inference analysis revealed a positive association between MRS and pathways potentially related to fibrolytic activity (r = 0.54; p = 0.07 and r = 0.56; p = 0.05 for butyrate metabolism and thiamine metabolism, respectively). In contrast, the metabolic pathway of starch degradation appeared negatively associated with MRS (r = −0.55; p = 0.06). The present findings suggest a potential contribution of the large intestine microbiota and dietary fibers digestion to exercise capacity in equine athletes.

Gut Microbiota Composition Positively Correlates with Sports Performance in Competitive Non-Professional Female and Male Runners

Article

Full-text available

Oct 2024

There is still a pressing need for further investigation to bridge the gap in understanding the differences in gut microbiota composition between female runners and their male counterparts. We aimed to determine the gut microbiota composition in competitive non-professional female and male runners and to correlate the gut bacteria to performance. Our study included 40 subjects, of which 22 were runners (13 males and 9 females) and 18 control subjects (9 males and 9 females, representing the general population who perform light physical activity with a weekly running volume of ≤5 km per week). Fecal specimens were collected and analyzed for taxonomic profiling to compare species’ relative abundances between males and females based on the results of 16SrRNA analysis. Bacterial alpha and beta diversity were assessed to determine the differences in microbial composition between runners and controls, and between sexes. Each participant underwent a maximal oxygen consumption test and a time-to-exhaustion test at 85% of the measured VO2max. Blood lactate was collected every 5 min during the tests. Bacterial alpha diversity showed a significant difference (p = 0.04) between runners and controls. Taxonomic analysis of gut microbiota composition showed a lower Enterobacteriaceae abundance and a higher Methanosphaera abundance in runners compared with the control group. Ten different bacteria (Methanosphaera, Mitsuokella, Prevotellaceae, Megamonas, Rothia, Oscillospira, Bacteroides, Odoribacter, Blautia massiliensis, Butyricicoccus_pullicaecorum) were positively correlated with exercise (VO2max, lactate blood levels, time to exhaustion, and weekly training volume). We found no significant differences in the gut microbiota composition between male and female runners. Gut microbiota composition positively correlates with sports performance in competitive non-professional female and male runners, and female runners show similar gut microbiome diversity to male runners.

Nutritional Modulation of the Gut–Brain Axis: A Comprehensive Review of Dietary Interventions in Depression and Anxiety Management

Article

Full-text available

Oct 2024

Mental health is an increasing topic of focus since more than 500 million people in the world suffer from depression and anxiety. In this multifactorial disorder, parameters such as inflammation, the state of the microbiota and, therefore, the patient’s nutrition are receiving more attention. In addition, food products are the source of many essential ingredients involved in the regulation of mental processes, including amino acids, neurotransmitters, vitamins, and others. For this reason, this narrative review was carried out with the aim of analyzing the role of nutrition in depression and anxiety disorders. To reach the review aim, a critical review was conducted utilizing both primary sources, such as scientific publications and secondary sources, such as bibliographic indexes, web pages, and databases. The search was conducted in PsychINFO, MedLine (Pubmed), Cochrane (Wiley), Embase, and CinAhl. The results show a direct relationship between what we eat and the state of our nervous system. The gut–brain axis is a complex system in which the intestinal microbiota communicates directly with our nervous system and provides it with neurotransmitters for its proper functioning. An imbalance in our microbiota due to poor nutrition will cause an inflammatory response that, if sustained over time and together with other factors, can lead to disorders such as anxiety and depression. Changes in the functions of the microbiota–gut–brain axis have been linked to several mental disorders. It is believed that the modulation of the microbiome composition may be an effective strategy for a new treatment of these disorders. Modifications in nutritional behaviors and the use of ergogenic components are presented as important non-pharmacological interventions in anxiety and depression prevention and treatment. It is desirable that the choice of nutritional and probiotic treatment in individual patients be based on the results of appropriate biochemical and microbiological tests.

The Effect of Exercise on Depression and Gut Microbiota: Possible Mechanisms

Article

Nov 2024
BRAIN RES BULL

Targeting Cognitive Resilience through Prebiotics: A Focused Perspective

Article

Full-text available

Nov 2024

Complex gut–brain interactions underlying inflammatory bowel disease-related depression have translational implications in regenerative medicine: a narrative review

Article

Sep 2024

Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, are chronic gastrointestinal disorders characterized by relapsing intestinal inflammation. In addition to gastrointestinal symptoms, patients with inflammatory bowel diseases experience a disproportionately high prevalence of depression and other neuropsychiatric comorbidities. The gut–brain axis, a bidirectional communication system between the gut and brain, has emerged as a potential pathogenic link underlying this aberrant mind–gut interplay. This review synthesizes the growing evidence implicating gut–brain axis dysregulation as a central mechanism bridging intestinal inflammation and the development of depression in patients with inflammatory bowel diseases. Regenerative medicine offers promising new avenues for addressing these complex conditions. By focusing on regenerative therapies that target the gut–brain axis, we explore new approaches that could repair or restore normal function in both the gut and brain. These therapies might alleviate chronic intestinal inflammation and restore proper gut–brain signaling via neural, immune-mediated, endocrine, and microbiome-related pathways, ultimately reversing the neurochemical, structural, and functional brain abnormalities implicated in depressive neuropathology. Unraveling the complex gut–brain interactions underlying inflammatory bowel disease-related depression through regenerative medicine has profound translational implications, paving the way for transformative diagnostic and therapeutic paradigms that address the multisystemic burden of these chronic debilitating conditions holistically.

Comparing the Impact of Continuous Endurance and High-intensity Interval Training on Cecal Butyrate and Propionate Levels in Diabetic Rats Induced by High-fat Diet

Article

Full-text available

Sep 2024

Background: Dysbiosis and metabolic disorders of the microbiota, often caused by an imbalance in the intestinal microbial composition, are significant issues linked to immobility, obesity, and diabetes. Physical exercise is recognized for its role in managing these symptoms by regulating the composition and metabolites of the intestinal microbiota, thereby improving gut health and overall metabolic function. Objectives: This study aimed to investigate and compare the effects of continuous endurance training (CET) and high-intensity interval training (HIIT) on two key cecal microbiota metabolites, butyrate and propionate, in diabetic rats. Methods: Forty-five male Wistar rats were made diabetic by a high-fat diet and were trained under CET and HIIT exercise protocols. Cecal tissue samples were taken from the rats to evaluate the effect of exercise, and the levels of two microbial metabolites, butyrate and propionate, were measured using the high-performance liquid chromatography (HPLC) method. Results: Among the exercise patterns studied, HIIT significantly improved the concentrations of butyrate and propionate, while CET showed no effect on these metabolites. Conclusions: Our findings suggest that, unlike CET, HIIT may effectively mitigate metabolic disturbances resulting from gut dysbiosis in diabetic patients. However, any definitive conclusion about the effects of CET and HIIT exercises on intestinal microbial metabolites necessitates further comprehensive tests on other metabolites and an examination of additional supporting evidence, such as changes in the composition of the intestinal microbiome.

Fecal microbiota transplantation confers beneficial metabolic effects of diet and exercise on diet-induced obese mice

Article

Full-text available

Oct 2018

Diet and exercise are conventional methods for controlling body weight and are linked to alterations in gut microbiota. However, the associations of diet, exercise, and gut microbiota in the control of obesity remain largely unknown. In the present study, using 16S rRNA amplicon sequencing and fecal microbiota transplantation (FMT), normal fat diet (NFD), exercise and their combination resulted in improved metabolic profiles in comparison to sedentary lifestyle with high fat diet (HFD). Moreover, diet exerted more influence than exercise in shaping the gut microbiota. HFD-fed mice receiving FMT from NFD-exercised donors not only showed remarkably reduced food efficacy, but also mitigated metabolic profiles (p < 0.05). The transmissible beneficial effects of FMT were associated with bacterial genera Helicobacter, Odoribacter and AF12 and overrepresentation of oxidative phosphorylation and glycolysis genes. Our findings demonstrate that the beneficial effects of diet and exercise are transmissible via FMT, suggesting a potential therapeutic treatment for obesity.

Six-Week Endurance Exercise Alters Gut Metagenome That Is not Reflected in Systemic Metabolism in Over-weight Women

Article

Full-text available

Oct 2018

Recent studies suggest that exercise alters the gut microbiome. We determined whether six-weeks endurance exercise, without changing diet, affected the gut metagenome and systemic metabolites of overweight women. Previously sedentary overweight women (n = 19) underwent a six-weeks endurance exercise intervention, but two were excluded due to antibiotic therapy. The gut microbiota composition and functions were analyzed by 16S rRNA gene amplicon sequencing and metagenomics. Body composition was analyzed with DXA X-ray densitometer and serum metabolomics with NMR metabolomics. Total energy and energy-yielding nutrient intakes were analyzed from food records using Micro-Nutrica software. Serum clinical variables were determined with KONELAB instrument. Soluble Vascular Adhesion Protein 1 (VAP-1) was measured with ELISA and its' enzymatic activity as produced hydrogen peroxide. The exercise intervention was effective, as maximal power and maximum rate of oxygen consumption increased while android fat mass decreased. No changes in diet were observed. Metagenomic analysis revealed taxonomic shifts including an increase in Akkermansia and a decrease in Proteobacteria. These changes were independent of age, weight, fat % as well as energy and fiber intake. Training slightly increased Jaccard distance of genus level β-diversity. Training did not alter the enriched metagenomic pathways, which, according to Bray Curtis dissimilarity analysis, may have been due to that only half of the subjects' microbiomes responded considerably to exercise. Nevertheless, tranining decreased the abundance of several genes including those related to fructose and amino acid metabolism. These metagenomic changes, however, were not translated into major systemic metabolic changes as only two metabolites, phospholipids and cholesterol in large VLDL particles, decreased after exercise. Training also decreased the amine oxidase activity of pro-inflammatory VAP-1, whereas no changes in CRP were detected. All clinical blood variables were within normal range, yet exercise slightly increased glucose and decreased LDL and HDL. In conclusion, exercise training modified the gut microbiome without greatly affecting systemic metabolites or body composition. Based on our data and existing literature, we propose that especially Akkermansia and Proteobacteria are exercise-responsive taxa. Our results warrant the need for further studies in larger cohorts to determine whether exercise types other than endurance exercise also modify the gut metagenome.

Butyrate and Dietary Soluble Fiber Improve Neuroinflammation Associated With Aging in Mice

Article

Full-text available

Aug 2018

Aging results in chronic systemic inflammation that can alter neuroinflammation of the brain. Specifically, microglia shift to a pro-inflammatory phenotype predisposing them to hyperactivation upon stimulation by peripheral immune signals. It is proposed that certain nutrients can delay brain aging by preventing or reversing microglial hyperactivation. Butyrate, a short-chain fatty acid (SCFA) produced primarily by bacterial fermentation of fiber in the colon, has been extensively studied pharmacologically as a histone deacetylase inhibitor and serves as an attractive therapeutic candidate, as butyrate has also been shown to be anti-inflammatory and improve memory in animal models. In this study, we demonstrate that butyrate can attenuate pro-inflammatory cytokine expression in microglia in aged mice. It is still not fully understood, however, if an increase in butyrate-producing bacteria in the gut as a consequence of a diet high in soluble fiber could affect microglial activation during aging. Adult and aged mice were fed either a 1% cellulose (low fiber) or 5% inulin (high fiber) diet for 4 weeks. Findings indicate that mice fed inulin had an altered gut microbiome and increased butyrate, acetate, and total SCFA production. In addition, histological scoring of the distal colon demonstrated that aged animals on the low fiber diet had increased inflammatory infiltrate that was significantly reduced in animals consuming the high fiber diet. Furthermore, gene expression of inflammatory markers, epigenetic regulators, and the microglial sensory apparatus (i.e., the sensome) were altered by both diet and age, with aged animals exhibiting a more anti-inflammatory microglial profile on the high fiber diet. Taken together, high fiber supplementation in aging is a non-invasive strategy to increase butyrate levels, and these data suggest that an increase in butyrate through added soluble fiber such as inulin could counterbalance the age-related microbiota dysbiosis, potentially leading to neurological benefits.

Gut Microbiota Composition Is Related to Cardiorespiratory Fitness in Healthy Young Adults

Article

Full-text available

Jul 2018

Bacteria residing in the human gastrointestinal (GI) tract has a symbiotic relationship with its host. Animal models have demonstrated a relationship between exercise and gut microbiota composition. This was the first study to explore the relationship between cardiorespiratory fitness (maximal oxygen consumption, VO2max) and relative gut microbiota composition [Firmicutes to Bacteroidetes ratio (F/B)] in healthy young adults in a free-living environment. Twenty males and 18 females (25.7±2.2 y), who did not take antibiotics in the last 6 months, volunteered for this study. VO2max was measured using a symptom-limited graded treadmill test. Relative microbiota composition was determined by analyzing DNA extracted from stool samples using Quantitative Polymerase Chain Reaction (qPCR) that specifically measured the quantity of a target gene (16s RNA) found in Firmicutes and Bacteroidetes. Relationships between F/B and potentially related dietary, anthropometric, and fitness variables were assessed using correlation analyses with appropriate Bonferroni adjustment (p<0.004). Average F/B ratio in all participants was 0.94±0.03. F/B ratio was significantly correlated to VO2max (r=0.48, p<0.003) but, no other fitness, nutritional intake, or anthropometric variables (p>0.004). VO2max explained ~22% of the variance of an individual's relative gut bacteria as determined by F/B ratio. These data support animal findings, demonstrating a relationship between relative human gut microbiota composition and cardiorespiratory fitness in healthy young adults. GI bacteria is integral in regulating a myriad of physiological processes, and greater insight regarding ramifications of exercise and nutrition on gut microbial composition may help guide therapies to promote human health.

A Prospective Metagenomic and Metabolomic Analysis of the Impact of Exercise and/or Whey Protein Supplementation on the Gut Microbiome of Sedentary Adults

Article

Full-text available

Apr 2018

The gut microbiota of humans is a critical component of functional development and subsequent health. It is important to understand the lifestyle and dietary factors that affect the gut microbiome and what impact these factors may have. Animal studies suggest that exercise can directly affect the gut microbiota, and elite athletes demonstrate unique beneficial and diverse gut microbiome characteristics. These characteristics are associated with levels of protein consumption and levels of physical activity. The results of this study show that increasing the fitness levels of physically inactive humans leads to modest but detectable changes in gut microbiota characteristics. For the first time, we show that regular whey protein intake leads to significant alterations to the composition of the gut virome.

Extensive impact of non-antibiotic drugs on human gut bacteria

Article

Full-text available

Mar 2018
NATURE

A few commonly used non-antibiotic drugs have recently been associated with changes in gut microbiome composition, but the extent of this phenomenon is unknown. Here, we screened more than 1,000 marketed drugs against 40 representative gut bacterial strains, and found that 24% of the drugs with human targets, including members of all therapeutic classes, inhibited the growth of at least one strain in vitro. Particular classes, such as the chemically diverse antipsychotics, were overrepresented in this group. The effects of human-targeted drugs on gut bacteria are reflected on their antibiotic-like side effects in humans and are concordant with existing human cohort studies. Susceptibility to antibiotics and human-targeted drugs correlates across bacterial species, suggesting common resistance mechanisms, which we verified for some drugs. The potential risk of non-antibiotics promoting antibiotic resistance warrants further exploration. Our results provide a resource for future research on drug-microbiome interactions, opening new paths for side effect control and drug repurposing, and broadening our view of antibiotic resistance.

The Madness of Microbiome: Attempting To Find Consensus "Best Practice" for 16S Microbiome Studies

Article

Full-text available

Mar 2018
APPL ENVIRON MICROB

The development and continuous improvement of high-throughput sequencing platforms has stimulated interest in the study of complex microbial communities. Currently, the most popular sequencing approach to study microbial community composition and dynamics is targeted 16S rRNA gene metabarcoding. To prepare samples for sequencing, there are a variety of processing steps, each with the potential to introduce bias at the data analysis stage. In this short review, key information from the literature pertaining to each processing step is described and consequently, general recommendations for future 16S rRNA gene metabarcoding experiments are made.

Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features

Article

Sep 2018
CELL

Empiric probiotics are commonly consumed by healthy individuals as means of life quality improvement and disease prevention. However, evidence of probiotic gut mucosal colonization efficacy remains sparse and controversial. We metagenomically characterized the murine and human mucosal-associated gastrointestinal microbiome and found it to only partially correlate with stool microbiome. A sequential invasive multi-omics measurement at baseline and during consumption of an 11-strain probiotic combination or placebo demonstrated that probiotics remain viable upon gastrointestinal passage. In colonized, but not germ-free mice, probiotics encountered a marked mucosal colonization resistance. In contrast, humans featured person-, region- and strain-specific mucosal colonization patterns, hallmarked by predictive baseline host and microbiome features, but indistinguishable by probiotics presence in stool. Consequently, probiotics induced a transient, individualized impact on mucosal community structure and gut transcriptome. Collectively, empiric probiotics supplementation may be limited in universally and persistently impacting the gut mucosa, meriting development of new personalized probiotic approaches.

Exercise Alters Gut Microbiota Composition and Function in Lean and Obese Humans

Article

Nov 2017

Purpose: Exercise is associated with altered gut microbial composition, but studies have not investigated whether the gut microbiota and associated metabolites are modulated by exercise training in humans. We explored the impact of six weeks of endurance exercise on the composition, functional capacity, and metabolic output of the gut microbiota in lean and obese adults with multiple-day dietary controls prior to outcome variable collection. Methods: Thirty-two lean (n=18 [9 female]) and obese (n=14 [11 female]), previously sedentary subjects participated in six weeks of supervised, endurance-based exercise training (3 days/wk) that progressed from 30 to 60 minutes/day and from moderate (60% of heart rate reserve [HRR]) to vigorous intensity (75% HRR). Subsequently, participants subsequently returned to a sedentary lifestyle activity for a six week washout period. Fecal samples were collected before and after six weeks of exercise, as well as after the sedentary washout period, with 3-day dietary controls in place prior to each collection. Results: β-diversity analysis revealed that exercise-induced alterations of the gut microbiota were dependent on obesity status. Exercise increased fecal concentrations of short chain fatty acids (SCFAs) in lean, but not obese, participants. Exercise-induced shifts in metabolic output of the microbiota paralleled changes in bacterial genes and taxa capable of SCFA production. Lastly, exercise-induced changes in the microbiota were largely reversed once exercise training ceased. Conclusion: These findings suggest that exercise training induces compositional and functional changes in the human gut microbiota that are dependent on obesity status, independent of diet and contingent on the sustainment of exercise.

Exercise training-induced modification of the gut microbiota persists after microbiota colonization and attenuates the response to chemically-induced colitis in gnotobiotic mice

Article

Sep 2017

Exercise reduces the risk of inflammatory disease by modulating a variety of tissue and cell types, including those within the gastrointestinal tract. Recent data indicates that exercise can also alter the gut microbiota, but little is known as to whether these changes affect host function. Here, we use a germ-free (GF) animal model to test whether exercise-induced modifications in the gut microbiota can directly affect host responses to microbiota colonization and chemically-induced colitis. Donor mice (n = 19) received access to a running wheel (n = 10) or remained without access (n = 9) for a period of six weeks. After euthanasia, cecal contents were pooled by activity treatment and transplanted into two separate cohorts of GF mice. Two experiments were then conducted. First, mice were euthanized five weeks after the microbiota transplant and tissues were collected for analysis. A second cohort of GF mice were colonized by donor microbiotas for four weeks before dextran-sodium-sulfate was administered to induce acute colitis, after which mice were euthanized for tissue analysis. We observed that microbial transplants from donor (exercised or control) mice led to differences in microbiota β-diversity, metabolite profiles, colon inflammation, and body mass in recipient mice five weeks after colonization. We also demonstrate that colonization of mice with a gut microbiota from exercise-trained mice led to an attenuated response to chemical colitis, evidenced by reduced colon shortening, attenuated mucus depletion and augmented expression of cytokines involved in tissue regeneration. Exercise-induced modifications in the gut microbiota can mediate host-microbial interactions with potentially beneficial outcomes for the host.