GUT MICROBES

2019, VOL. 10, NO. 5, 555–568

https://doi.org/10.1080/19490976.2018.1562268

REVIEW

Exercise influence on the microbiome–gut–brain axis

Alyssa Dalton, Christine Mermier, and Micah Zuhl
Department of Health, Exercise, and Sports Sciences, University of New Mexico, Albuquerque, NM, USA

ABSTRACT ARTICLE HISTORY

The microbiome in the gut is a diverse environment, housing the majority of our bacterial Received 8 August 2018
microbes. This microecosystem has a symbiotic relationship with the surrounding multicellular Revised 27 November 2018
organism, and a balance and diversity of specific phyla of bacteria support general health. When Accepted 9 December 2018
gut bacteria diversity diminishes, there are systemic consequences, such as gastrointestinal and KEYWORDS
psychological distress. This pathway of communication is known as the microbiome–gut–brain Exercise; gut; brain;
axis. Interventions such as probiotic supplementation that influence microbiome also improve probiotics;
both gut and brain disorders. Recent evidence suggests that aerobic exercise improves the microbiome–gut–brain axis
diversity and abundance of genera from the Firmcutes phylum, which may be the link between
the positive effects of exercise on the gut and brain. The purpose of this review is to explain the
complex communication pathway of the microbiome–gut–brain axis and further examine the role
of exercise on influencing this communication highway.

Introduction and fungi. The current review will specifically

emphasize the bacterial component of the gut.
The microbiome in the gut is a diverse environment,
In human adults, approximately 90% of the gut
housing the majority of our bacterial microbes.
bacteria belong to the Bacteroidetes and Firmicutes
Consisting of over 1,100 genera among different
phyla, whereas the minority bacteria belongs to
phyla, the gut epithelium harbors nearly 39 trillion
Proteobacteria, Actinobacteria, Fusobacteria, and
microbes which is a 1:1 ratio of microbes to eukar-
Verrucomicrobia phyla.17,18 The Firmicutes phylum
yotic cells in the human body.1,2 The gut micro-
contains over 250 genera of bacteria, including
biome promotes digestion and food absorption for
Lactobacillus and Clostridium, while Bacteroidetes
energy production, performs a fundamental role in
phylum includes around 20 genera, the most abun-
the function of the immune system,3-5 produces and
dant being Bacteroides.18 The gut bacterial commu-
communicates with hormonal products as an endo-
nity is maintained through the symbiotic
crine-like organ,6 and appears to have an impact on
relationship between both pathogenic and non-
brain function.7-12 The diverse roles of the micro-
pathogenic bacteria and can be demonstrated by
biome are mediated through production and release
balanced ratio of the Bacteroidetes or Firmicutes
of various molecules. For example, microbes are
phyla and other nondominant phyla.19,20
capable of producing short-chain fatty acids
Substantial shifts to the microbial communities in
(SCFAs) which are used as nutrients for colonocytes
response to dietary changes, antibiotics, or invasions
and brain microglia cells, support cholesterol meta-
of pathogens may cause a shift to a nonequilibrium,
bolism, and regulate various hormones involved in
or inflammatory state, and has important health
appetite.13,14 Gut bacteria are also capable of produ-
implications.21 Gut microbiome disruption is
cing enzymes that regulate inflammatory pathways
thought to play a key role in the development of
and amino acids that have both free radical generat-
several diseases including type 2 diabetes,8,22,23 irri-
ing and scavenging properties.15,16 The gut micro-
table bowel syndrome (IBS),24 cardiovascular
biome is not only comprised of bacteria, but houses
diseases,23 allergies, mood disorders,7,9,11, and many
other prokaryotes (i.e., Archaea) along with viruses
others via intestinal inflammation.3,6

CONTACT Micah Zuhl [email protected] Department of Health, Exercise, and Sports Sciences, University of New Mexico, Albuquerque, NM, USA
© 2019 Taylor & Francis Group, LLC
556 A. DALTON ET AL.

The gut has long been overlooked when it comes exercise may have the potential to reverse the con-
to human health and disease prevention. Emerging ditions associated with obesity, metabolic diseases,
research has proved that an imbalanced diet of poor diet, along with neural and behavioral
highly saturated fats, high sugar, and low fiber disorders.42-45 To date, the impact of exercise on
intake has a large influence on the composition of the relationship between the gut and the brain is
the microbiome.8 The alterations induced by poor unknown. Therefore, the purposes of this review
dietary habits contribute to gastrointestinal are to briefly introduce the complex interaction
(GI) dysfunction that may further lead to the devel- between the microbiome, gut, and brain and to
opment of inflammatory diseases.25 Interestingly, further explain how exercise impacts these rela-
a prebiotic intervention that promoted changes in tionships. For this review, we have chosen to
the microbiota of diabetic rats lowered inflamma- state this relationship as the microbiome–gut–
tion while improving glucose intolerance.26,27 brain axis where the composition of the gut micro-
Moreover, individuals diagnosed with inflamma- biota influences both the GI and central nervous
tory conditions such as IBS and obesity have been systems (CNSs).34,46 More specifically, alterations
found to have a comorbidity of lower cognitive to the microbiome may impact (both positively
function28,29 and higher instances of stress-related and negatively) GI (e.g., secretion, motility,
psychiatric symptoms, such as anxiety.30-32 In and integrity) and higher brain function (e.g.,
accordance, interventions that specifically treat neurotransmission, neurogenesis, and behavior),
neural disorders such as selective serotonin uptake and these influences may be bidirectional.34
inhibitors (SSRIs) have been shown to improve GI
function.33 These data have sparked curiosity
among investigators, which has led to a growth of Microbiome–gut–brain axis pathways of
communication
research into understanding the connection
between the GI tract and the brain.7,9,11,30,34 The relationship between the gut and the brain
Further interest has grown in discovering the role begins in utero as the CNS and the enteric nervous
of the microbiome in mediating the connection system (ENS) are derived from the same tissues
between the gut and brain. Altering the gut micro- during fetal development.7 The communication
biome through probiotic supplementation has between the gut and the brain is a bidirectional path-
improved symptoms of both psychological disor- way that is mediated through the autonomic ner-
ders (e.g., depression and anxiety) and cognition vous system (ANS) efferent and afferent signals via
and positively supports GI function.35-39 This the vagus nerve; neuroendocrine signaling through
demonstrates the complexity of the relationship the hypothalamic–pituitary–adrenal axis (HPA
between the gut microbiome and the brain. axis), and serotonin (5-HT) regulation.47-50 It has
Regular aerobic exercise has been shown to now been established that alterations of gut micro-
prevent age-related global brain atrophy and biome enact some influence on the communication
increases brain volume in the frontal lobes and between the gut and brain through these pathways.
left superior temporal lobe, which are important The vagus nerve serves a critical role in commu-
for cognition and control of attention and nication between the gut microbes and the brain, as it
memory.40 Moderate-intensity aerobic exercise connects the CNS to the ENS.51,52 The vagus nerve is
training has also promoted improvement (in able to communicate with gut microbiota in the ENS
older adults aged 60–79 years) in functional acti- and transfer vital information to the CNS where it is
vation in the brain which allows for increased deciphered, to then generate a response based on the
efficiency when completing tasks, as well as regu- information received. For example, if the information
lating behavior and mood.41 More recently, aero- received via the vagus nerve from the gut indicates an
bic exercise has been shown to impact the gut by imbalance in gut microbiome bacteria, the CNS will
increasing microbiome diversity and functional then decipher if an inflammatory response is neces-
metabolism in both humans and mice. Altering sary. Decreased vagus nerve activity has been asso-
the bacterial profiles and influencing the by- ciated with conditions such as IBD,53 IBS,54 and
products produced from gut bacteria through depression55-57 and is attributed to dysfunction of
 GUT MICROBES 557

gastric motility and gastric emptying.58 Specifically the gut microbiome is important in the adequate
targeted probiotic supplements that alter the micro- development of both the HPA axis and the CNS
biome have also been shown to improve brain func- during early life.64,69 While extremely complex,
tion, and this positive neural benefit is abolished when when a diverse and healthy microbiome communi-
a vagotomy procedure is performed among rodents.59 cates with the CNS, tighter HPA control occurs,
More specifically, mice induced with colitis demon- which may further promote both neural and GI
strated lower anxiety-like behavior after 21 days of growth through BDNF regulation.70,71
being fed a probiotic supplement containing Serotonin (5-HT) is a crucial neurotransmitter and
Bifidobacterium longum. The anxiolytic effect of hormone and is often known as one of the primary
Bifidobacterium longum was lost when vagotomized mood and cognition regulators.72 Lower platelet ser-
mice were fed the supplement. The authors concluded otonin receptor function is associated with higher
that the behavior benefits of the Bifidobacterium levels of anxiety and depression, while higher platelet
longum is vagally mediated.59 This provides evidence serotonin is associated with improved mood.73 It is
that vagal communication between the gut and brain also a major contributor to the modulation of intest-
is influenced by the release of molecules from the gut inal secretion and motility,74,75 as well as a key signal-
microbiota. ing molecule within the microbiome–gut–brain
The HPA axis regulates an organism’s response to axis.30,65 Recently, it has been demonstrated that indi-
a multitude of stressors (e.g., physical or mental).60,61 genous bacteria in the gut regulate serotonin synthesis
The HPA is influenced by the GI system through and release.76 In addition, germ-free animals have
a complex neural-immunoregulatory mechanism. demonstrated higher levels of serotonin in the hippo-
Afferent feedback from the gut via the vagus nerve campal region of the brain while showing lower
acts on the hypothalamus and hippocampus regions expression in the colon.76,77 This demonstrates that
of the brain, resulting in activation of the HPA.62 It the microbiome plays a role in the regulation of
also appears that disruption to the gut mucosal layer serotonin and may influence both brain and gut func-
via lipopolysaccharide (LPS) insult promotes the tion. It appears that various gut microbe strains
release of pro-inflammatory cytokines, which are synthesize serotonin and may be the reason why
capable of exaggerating HPA activation.47,63 HPA germ-free rodents have lower expression of 5-HT in
axis hyperresponsiveness and disturbances in the the gut. Other strains control tryptophan metabolism,
gut microbiome are found in those suffering from the precursor to 5-HT synthesis, and have been
both IBS and psychological disorders.61 This demon- shown to influence both tryptophan and serotonin
strates potential roles for the neuroendocrine system levels.78,79 For example, the Bacteroides fragilis bacter-
and the gut microbiome in the regulation of both the ium is a known consumer of tryptophan, and supple-
gut and brain. Rodents raised in a germ-free envir- mentation has been linked to improving intestinal
onment (no-microorganism exposure and no poten- wall stability, and also protection against CNS demye-
tial for gut microbiota colonization) from birth are linating disease.65,80,81 Autism spectrum disorder is
found to have an inflated release of adrenocortico- a developmental disorder that affects behavior and is
tropic hormone (ACTH) and corticosterone levels in commonly associated with GI symptoms. Autistic like
response to physical restraint stress exposure when mice demonstrated improved GI function and also
compared to free-living control rodents.6,34,48,64-66 began to resemble normal behaving animals after
The germ-free rodents also displayed lower expres- supplementation with Bacteroides fragilis.81
sion of brain-derived neurotrophic factor (BDNF) in In summary, the microbiome is capable of influen-
the hippocampal and cortex regions of the brain. cing both brain and gut function by modulating vagus
BDNF promotes neurogenesis and is vital for CNS nerve afferent feedback; influencing the hyperrespon-
growth and health.67 BDNF has also been shown to siveness of the HPA axis; and altering the regulation
be an important regulator of GI tight junction pro- of the tryptophan and serotonin synthesis pathways.
tein expression and regulation.68 Treatment with However, it is important to understand that other
Bifidobacterium ameliorated the exaggerated HPA communication channels in the gut–brain axis such
response in the germ-free rodents and restored as GABA-glutamate and catecholamines have been
BDNF levels in the brain.64 It has become clear that shown to be influenced by specific microbiota.82,83
558 A. DALTON ET AL.

Exercise effect on the microbiota–gut–brain of microbes that contribute to the biodiversity of the
axis bacteria in the gut.42-44,66 Exercise appears to be
a potential external influence on the capacity to
The bulk of previous exercise research on GI phy- alter the gut biodiversity in both quantitative and
siology has shown a negative effect. For example, in qualitative ways.6 Exercise alterations to the gut
several studies from our group and others, intense microbiome may provide a link to the exercise-
exercise leads to an increase in intestinal permeabil- related benefits on GI function, mood, and higher
ity, GI damage, and mild endotoxemia.84-86 brain centers. Figure 1 highlights the impact of
However, targeted exercise therapies have been exercise on the microbiome, and how alterations
developed to treat those suffering from IBS with may mediate improvements in both the gut and
reported improvements in symptoms of the brain.
disorder.87 Exercise also promotes cognition and Research conducted among volunteers from the
improved symptoms of both mood and psychologi- American Gut Project95 concluded that those who
cal disorders among humans. Cognitive improve- exercised at a higher frequency demonstrated
ments have been observed among stroke patients, diversity in the Firmcutes phylum (specifically,
while symptoms of depression and schizophrenia Faecalibacterium prausnitzii and species from the
have also been improved after aerobic exercise genus Oscillospira, Lachnospira, and Coprococcus).
training.88-90 Interestingly, the improvements Athletes have been shown to exhibit higher diver-
observed among IBS patients after exercise were sity of gut microorganisms compared to nonath-
linked to changes in mental health and emotion.87 letes. More specifically, in a group of professional
Evidence suggests that the bacterial diversity of the rugby players, 22 phyla were detected, while only
gut contributes to the disordered state of GI disor- 11 phyla were identified in age-matched low BMI
ders by negatively impacting GI function and the control and 9 phyla in an age-matched high BMI
psychological state.91,92 Altering the microbiome control. The distinct phyla among the athletes
through probiotic supplements improves both GI correlated with both dietary protein intake and
integrity and mood among IBS patients.92,93 creatine kinase, suggesting that diet and exercise
Probiotic supplements also reduced stress-induced facilitate diversity in the gut. The researchers iden-
GI symptoms (abdominal pain and nausea) among tified higher proportions of the Firmicutes phyla
participants with a history of elevated stress.94 and lower Bacteroidetes phyla in the athlete group
Exciting research within the last 5 years has demon- compared to the high BMI control.42 While the
strated that exercise promotes a diverse community athlete group had greater diversity than the low

Figure 1. The role of exercise in the microbiome–gut–brain axis. Exercise and the gut microbiome have been independently shown
to improve symptoms of IBS and stabilize the TJ barrier and have also been linked to decrease psychological disorders (e.g.
depression, anxiety), promote neurogenesis (through BDNF), and improve HPA axis control. It has been demonstrated that aerobic
exercise caused greater diversity in the microbiome along with increasing genera of the Firmicutes phylum, which produce short-
chain fatty acids. In addition, athletes have demonstrated higher levels of the Akkermansia genus, which has been linked to
metabolic and neural diseases. The extent to which the effect of exercise on the gut and brain is mediated through alterations in the
microbiome is unknown. The dotted line represents a proposed mechanism. Solid lines represent known mechanisms. BDNF – brain-
derived neurotropic factor, SCFA – short-chain fatty acids, ZO-1 – zona occluden-1 protein, HPA axis – hypothalamic–pituitary–
adrenal axis, TJ – tight junction.
 GUT MICROBES 559

BMI control, it was difficult for the researchers to aerobic fitness (VO2max) and fecal SCFAs, indi-
identify specific bacteria that help to understand cating that more aerobically fit humans produce
the role of extreme exercise on the microbiome in higher rates of SFCAs.101 Total dietary protein
this study. Interestingly, both the athletes and low intake was also a significant contributor to the
BMI group demonstrated a higher proportion of diversity and functional changes (SFCA produc-
the Akkermansia genus (Verrucomicrobia phy- tion) in the gut, further highlighting the role of
lum), which has been negatively associated with diet. Higher SFCA production is attributed to
metabolic dysfunction in humans and rodents.42 many health benefits, including protection against
The administration of Akkermansia has been inflammation and atherosclerosis.102 SCFAs pro-
shown to reversed diet-induced metabolic disor- duced from the microbiome also appear to provide
ders in obese mice.96 The Akkermansia genus has nutrients to brain microglia to support healthy
also been linked to cognitive impairment as maturation and function.103 In summary, a link
a result of poor dietary habits.97 Mice demon- has been established between the functional by-
strated a 5.4-fold reduction in Akkermansia and products (i.e., SFCA) of the gut microbiome and
associated behavioral decline in response to the healthy behaviors (exercise and diet).99
Western diet (high fat and sugar intake).98 While The bulk of research examining the role of exercise
the link between exercise changes to the gut interventions on changes in the gut microbiome has
microbiome and resulting changes in brain func- been performed in rodent models. Kang et al.104 ana-
tion is unknown, the alterations among athletes lyzed changes in the gut bacteria among mice after
appear to be a result of exercise and dietary beha- a 16-week exercise program (forced wheel running
viors, which may provide protection against both 5 days/week) compared to a high-fat diet group.104
metabolic and cognitive decline. Exercise appeared to increase the bacteria of phylum
In a follow-up study, the same group of Firmicutes and lower Bacteroidetes, which was sur-
researchers confirmed the microbial diversity prisingly similar to the changes observed in the high-
among elite rugby athletes compared to nonactive, fat diet group. Conversely, Evans et al.105 reported
age-matched control and again demonstrated opposite findings with lower Firmicutes and higher
higher levels of Akkermansia.99 The researchers Bacteroidetes after 12 weeks of voluntary wheel run-
also performed metabolomic phenotyping of the ning. The group also demonstrated exercise preven-
microbiome to further understand the differences tion of high-fat diet-induced obesity and suggested
between athletes and controls at the functional a microbial altering mechanism of exercise on avert-
metabolic level. The athletes reported higher activ- ing high-fat diet-related obesity.105 The differential
ity of several pathways, including amino acid results between the Kang and Evans groups may be
synthesis, and carbohydrate metabolism. As attributed to the forced vs. voluntary wheel running
a result, athletes demonstrated an enriched profile protocols utilized in the studies, respectively (dis-
of SCFAs, indicating greater production and host cussed in next section). A link has been made between
absorption rates. Identified SFCAs in the athletes low gut Bacteriodetes and obesity and further sup-
were acetate, propionate, and butyrate, which are ported by increased Bacteriodetes in response to
produced by gut microbes from protein, fibers, weight loss among obese individuals.106 The richness
and nondigestible starches.100 The researchers and diversity of the gut microbiome has been corre-
attributed the differences between athletes and lated with various metabolic markers where low rich-
controls to heavy physical activity and the asso- ness corresponds with higher adiposity, insulin
ciated diet. They highlighted the impact of the resistance, and dyslipidemia.107 Exercise is an estab-
high protein and fiber diet among the athletic lished treatment for metabolic disorders, and these
group and the resulting metabolism by gut results may indicate that exercise-related changes in
microbes. In support of these findings, Estaki et - the gut microbiome may support metabolic health.
al.101 distinctly identified an association between In a short voluntary wheel running exercise proto-
cardiorespiratory fitness and microbiome function col (6 days), Queipo-Ortuno et al.108 reported an
rather than diversity of specific bacterial taxa. increase in genera Lactobacillus and Blautia coccoides-
A strong relationship was observed between Eubacterium rectale from the Firmicutes phylum,
560 A. DALTON ET AL.

along with genus Bifidobacterium from the These findings suggest that aerobic exercise affects
Actinobaceria phylum. All three genera are capable the content and diversity of the gut microbiome in
of producing SCFAs,109 which may be considered humans and may additionally raise the question
a functional change in the gut microbiome as about how gut microbes influence adaptations to
a result of exercise. Queipo-Ortuno et al.108 also exercise.
posted a positive association between Lactobacillus The identified “exercise” genera by Allen et al.114
and Bifidobacterium and serum leptin levels in the were all producers of SCFAs and more specifically
animals. Leptin is a hormone secreted from adipose butyrate. Butyrate and other SFCAs are known
tissue and helps to control appetite and eating energy substrates for colonocytes, with butyrate
behavior.110 These results demonstrate that exercise being the primary energy source.115,116 This may
alterations to the gut microbiome are related to diet- explain why exercise improves symptoms and
ary food intake and may indicate a connection reduces the risk for IBS and colon cancer.117
between exercise, the gut, and behavioral change. Further, butyrate has been shown to stimulate
Several recent exercise intervention studies have neural proliferation in the dentate gyrus brain
been conducted among human subjects. While the regions of mice and has also been used to induce
primary aim of this review is to assess the impact of neurogenesis after ischemic brain insult in adult
exercise training on the gut microbiome. Zhao et al.- rodents.118,119 These results may provide a link
111 between exercise-induced microbial SCFA produc-
analyzed fecal samples before and after a half-
marathon event among human participants. An tion and improvements in both brain and GI func-
increase in the richness of the Actinobacteria phylum tion. However, it is unknown if the positive benefits
was reported with a notable correlation between the of exercise on gut and brain are mediated through
Coriobacteriaceae family and several metabolites. adjustments to the microbiome (see Figure 1).
Coriobacteriaceae has been associated with higher The limited amount of research explaining how
levels of high-density lipoprotein (HDL) and meta- exercise influences the microbiome has indicated
bolic improvements, and the researchers identified that genera from the Firmicutes phylum appear to
the change in bacteria as a potential mechanism for be the most responsive to exercise-induced
exercise-induced health benefits.112,113 These results changes. Given that the Firmicutes phylum con-
indicate that an acute bout of exercise, while extreme sists of over 250 genera, it is difficult to under-
(i.e., half-marathon) has a profound impact on the stand which genera lead to systemic inflammation
gut microbiome. and which lead to a healthy gut environment. The
In the first known human exercise study, Allen work from Allen et al.114 has implied that genera
et al.114 compared microbiota changes between that produce SCFA appear to respond to exercise;
lean and obese humans before and after a 6-week however, this is the only known study among
aerobic exercise program and further evaluated humans to evaluate changes after an aerobic exer-
changes after a period of de-training. Exercise cise intervention, and then upon cessation of exer-
caused changes in gut microbiome diversity and cise. In the only other human exercise study,
microbial production of SCFAs among both the Cronin et al.120 reported minimal change in gut
lean and obese subjects. The authors aimed to bacterial diversity among healthy male and females
identify groups of bacteria that responded to exer- who participated in an 8-week combined aerobic
cise training and identified the Faecalibacterium, and resistance exercise program. The conflicting
Lachnospira, Clostridia, and Roseburia genera, results may be due to the exercise regimen where
which are all part of the Firmicutes phylum. the aerobic training program in the Allen et al.114
These genera increased in abundance in response study appeared to be more vigorous, and 100%
to exercise training and returned to baseline upon compliance was reported. Importantly, Cronin et -
cessation. A notable finding was that changes in al.120 implemented a nonexercise control to accu-
the gut were associated with changes in lean mass rately assess and compare sedentary and exercise
and reduction in fat mass, meaning that shifts in behavior. They concluded that while the gut
microbial content were more substantial among microbiome is adaptable, 8 weeks of exercise may
those subjects that demonstrate these changes. not be enough stimulus to enact change. These
 GUT MICROBES 561

studies have advanced the field and future work is results in apoptosis (death of cells) in mice.
needed to fully characterize how the microbiome Decreased levels of BDNF in the hippocampus
adapts to exercise, and other various forms of have also been associated with anxiety and depres-
physical activity. sion and is often comorbid with gut inflammatory
diseases, such as IBS, and or inflammatory-bowel
disease (IBD).8,133 Oral supplementation with
Exercise influences the microbiome–gut– Bifidobacterium has been shown to increase
brain axis pathways of communication
BDNF expression in the brains of rodents, while
As mentioned previously, the vagus nerve is at the aerobic exercise in piglets has also been shown to
interface of the microbiome–gut–brain axis. increase Bifidobacterium in the gut.64,134 Antibiotic
Altered vagus nerve activation is commonly found treatments that killed gut bacteria also delayed the
in patients with both GI (IBS, IBD) and psycholo- growth of brain cells in the hippocampus regions
gical disorders (depression).121,122 Various forms of of mice.135 Both probiotics and aerobic exercise
exercise, including yoga and aerobic exercise train- individually rescued the decline in neurogenesis
ing, have been shown to improve parasympathetic and cognitive function among mice treated with
tone.123 Meta-analytical studies have identified the antibiotic.135 However, it is unknown if the
yoga as a proven mode of exercise to improve exercise effects on brain neurogenesis and cogni-
symptoms of IBS and depression,124,125 which may tion are mediated through Bifidobacterium.136
be partially mediated by autonomic influences. As Elevated HPA axis activation and gut–microbiome
previously discussed, alterations in the gut micro- disruption is seen when an exercising individual
biome affect vagal communication between the gut exceeds 60% of maximum oxygen uptake (VO2max)
and brain.126 An intact vagus nerve is critical for the or during prolonged exercise (>90 min).
benefits of probiotics supplements containing Psychological stress, such as the kind experienced by
strains of Bifidobacterium and Lactobacillus to be athletes pre-competition, has also led to an increased
effective.55 Further, any mediating effect of probio- HPA axis activation and greater gut disruption.10
tics on the HPA axis and depression-related symp- Likewise, research in mice has found that moderate
toms are abolished through the vagotomy forced treadmill running (8–12 m/min at a 5% grade
procedure.127 Therefore, it is logical to suggest for 40 min, 5 times per week) exacerbated colitis
that any alterations that exercise may have on the symptoms when compared to voluntary exercise,
diversity and expression of gut flora would poten- which attenuated symptoms.137 The researchers con-
tially be manifested through influence on vagal cluded that the forced exercise may have been per-
communication between the gut and brain. ceived as a psychological stressor by the mice, whereas
Unfortunately, empirical evidence currently does the voluntary wheel running is a conscious decision.
not exist to verify this conclusion. Hyperresponsive HPA axis appears to be influenced
Improvements in brain structure and function by the diversity of the gut microbiome where the lack
have been documented as an adaptation to repeti- of, or absence of bacteria, caused robust HPA activa-
tive aerobic exercise.40,128,129 Regular moderate- tion in response to psychological stress.64
intensity aerobic exercise prevents age-related Supplementation with Bifidobacterium species
brain volume loss and increased brain volume in reversed HPA overactivation and alleviated symp-
areas responsible for cognition and control of toms of anxiety and distress among rodents and
attention and memory.40 The positive benefits of humans, respectively.35 While previously noted, the
exercise on neural function appear to be mediated Bifidobacterium strains are influenced by aerobic
through regulation of BDNF. BDNF is central in exercise, where animals with free access to wheel
the growth and the survival of striatal neurons in running showed increased numbers of
108
the brain, and it also plays a critical role in reg- Bifidobacterium. Furthermore, force wheel running
ulating mood disorders, along with learning and resulted in reduced levels of Lactobacillus, which is
memory.34,130,131 According to Linnarsson et al.,132 important for protection against disease-causing
BDNF is known for its protective role in the adult microorganisms.138 It is important to mention that
brain, because the genetic deletion of this protein microbiome-altering effect of voluntary wheel
562 A. DALTON ET AL.

running has only been shown in male mice, whereas exercise can be a therapeutic factor and strategy for
null findings were reported in a combined cohort of both psychological and GI disorders. The main
male and female mice.138,139 However, both voluntary identified phyla that respond to exercise are
and forced exercise appear to influence the average Firmicutes and Actinobacteria, which contain the
operational taxonomic units (OTUs) of several micro- Lactobacillus and Bifidobacterium genera, respec-
bial species. For example, force running increased tively. In addition, the SCFA-producing genera
Ruminococcus, Butyrivibrio, and Oscillospira, which from the Firmicutes phylum also appear to increase
are all within Firmicutes phylum. Of note, many of in response to exercise. Future work should target
these various species are being considered as psycho- underlying mechanisms of how specifically exercise
biotics due to their role in neuropsychiatric influences the microbiome, and the mediators
disorders.140 In summary, it appears that the psycho- involved in the gut–brain axis. This may lead to
logical state of exercise influences the microbiome, the development of various treatment combina-
and these changes may further impact the HPA axis tions (exercise + probiotics) to ameliorate (or
regulation and mood disorder symptoms. improve) specific disease states.
Aerobic exercise has been shown to also influence
serotonin regulation. In rats, 5-HT synthesis and
metabolism increased in both the brain stem and the Author contributions
hippocampus in response to exercise,141 and this AD, CM, and MZ all participated in manuscript develop-
increase in 5-HT resulted in the reduction of depres- ment, design, and drafting.
sive and anxiety symptoms.142 Wipfili et. al.142
described the effects of exercise as similar to the
those of SSRIs used to treat depression and anxiety. Disclosure of Potential Conflicts of Interest
The following bacteria in the gut microbiome have
No potential conflicts of interest were disclosed.
been found to produce serotonin: Lactococcus lactis,
Lactobacillus plantarum, Streptococcus thermophile,143
Morganella morganii, and Klebsiella pneumonia.144 Funding
Unfortunately, there are no previous studies that thor-
This research did not receive any specific grant from funding
oughly examined if exercise has any influence on agencies in the public, commercial, or not-for-profit sectors.
these specific strains. Because some of these seroto-
nin-producing strains stem from the lactobacilis gen-
era (which is a component of Firmicutes phyla), References
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