Received: 27 December 2022 Revised: 27 April 2023 Accepted: 8 May 2023

DOI: 10.1002/mco2.304

H IGH LIGH TS

The microbiota–gut–brain axis regulates motivation

for exercise

Wenhuan Sun1,2 Zhenjiang Bai1,∗ Fangfang Zhou2,∗

1 Pediatric Intensive Care Unit, Children’s Hospital of Soochow University, Suzhou, China
2 Institutes of Biology and Medical Science, Soochow University, Suzhou, China

∗ Correspondence

Zhenjiang Bai, Pediatric Intensive Care Unit, Children’s Hospital of Soochow University, Suzhou 215025, P. R. China.
Email: bbyshu@hotmail.com
Fangfang Zhou, Institutes of Biology and Medical Science, Soochow University, Suzhou 215123, P. R. China.
Email: zhoufangfang@suda.edu.cn

Funding information
National Natural Science Foundation of China, Grant/Award Number: U20A20393; National Science Fund for Distinguished Young Scholars,
Grant/Award Number: 32125016

In a recent study published in Nature, Dohnalová et al.1
found that the motivation for long-term physical activity in
mice is not entirely driven by the brain, it is also regulated
by gut microbes. They reported that mice with proficient
running capabilities greatly benefitted from two types of
gut bacteria. Furthermore, it was discovered that these
bacteria stimulate enteric nerves by generating fatty acid
amides (FAA), which are diminutive molecule metabolites
that elevate the ventral striatum of the brain, subsequently
heightening the levels of dopamine in the body, thus
promoting a propensity to engage in physical exercise.
This discovery sheds light on the gut-to-brain pathway,
explaining why some bacteria boost athletic performance
(Figure 1).
Like other mammals, humans are inhabited by trillions
of microbes, including bacteria, viruses, and fungi, collec-
tively known as commensal flora. In a sense, “human”
is a multicomponent complex composed of the human
body and symbiotic flora. There are large numbers of
parasitic microorganisms in the human gut. Gut microor-
ganisms affect human obesity, enteritis, autoimmune dis-
eases, responses to cancer treatment drugs, and even life
expectancy. The gut microbiota influences the physiologi-
cal characteristics of the host during the earliest stages of
life. Alterations in gut microbiota may damage key pro-
cesses in the development of organ systems, including
the brain. Accumulating evidence has revealed the degree
of interdependence between humans and human gut
microbiota, emphasizing the importance of the brain–gut
axis.2
Regular exercise is increasingly being prescribed as an
adjunctive therapy for a variety of human diseases.3 Poor
fitness and physical inactivity are leading causes of chronic
non-communicable diseases (CNCDs) such as heart dis-
ease, stroke, type 2 diabetes, chronic respiratory disease,
and some cancers,4,5 highlighting the urgent need for tar-
geted efforts to reverse this trend. To identify factors that
determine exercise performance, the authors1 focused on
genome sequences, gut bacterial species, blood metabo-
lites, and other data from multiple mouse models with
different genetic backgrounds and assessed their relative
contribution to exercise performance. They then measured
the daily voluntary wheel movement and endurance of
the mice. These experimental data were then analyzed
by machine learning to find the correlation between the
physiological parameters and the exercise ability of mice
in order to explain the huge differences in running per-
formance between individuals. The team was surprised to

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https://doi.org/10.1002/mco2.304
2 of 3 SUN et al.

F I G U R E 1 Gut microbiota containing Eubacterium and Coprococcus can secrete fatty acid amides, like N-oleoylethanolamide (OEA),
which stimulate CB1 and TRPV1 receptors in the dorsal root ganglia. This prompts a decrease in monoamine oxidase (MAO) expression in the
brain’s striatum region, leading to more dopamine release and promoting exercise desire. The CB1 and TRPV1 receptors can be targeted to
facilitate or block gut–brain–motor signaling axis. Brain cartoon images used were obtained from Scidraw.io.

find that genes accounted for only a small portion of these
differences in athletic performance, whereas the composi-
tion of the bacterial community alone predicted running
performance with high accuracy, suggesting that gut bac-
teria drive athletic performance. Moreover, depletion of
gut bacteria through antibiotic treatment reduces exercise
tolerance. Transferring the gut microbiota from high-
performing mice to germ-free mice increased the function-
ing capacity of the recipients to a level that matched that of
the microbiome sample donors. Furthermore, the authors
have disclosed that the gut microbiota exerts an impact on
exercise performance by means of striatal activation, as evi-
denced by the results of single-nucleus RNA-sequencing
(RNA-seq) analysis of the striatum.
Using different classes of antibiotics, the authors iden-
tified two gut bacteria that were strongly associated with
better exercise performance: Eubacterium and Copro-
coccus. Furthermore, utilizing untargeted metabolomics,
the metabolites in the gut linked to these particular
intestinal bacteria were identified as FAAs, notably N-
oleoylethanolamide (OEA). FAA bind to the endogenous
cannabinoid receptor CB1 and stimulate the dorsal root
ganglia (DRG) to express the vanilloid receptor TRPV1 in
the gut, which connects to the brain through the spine.
During exercise, the intestinal sensory nerves expressed
CB1 receptors are stimulated, leading to the inhibition of
monoamine oxidase (MAO) expression, which degrades
dopamine and other neurotransmitter molecules in the
ventral striatum region of the brain, prompting the release
of neurotransmitter dopamine. The striatum is a key node
in the brain’s reward and motivation network; therefore,
higher dopamine levels in this region during exercise can
increase the desire to exercise and improve athletic perfor-
mance. Furthermore, the authors discovered that bouts of
dopamine triggered by physical exercise activate particular
neuronal subpopulations in the striatum area of the brain.
Inhibition of dopamine signaling reduces exercise tol-
erance, suggesting that exercise-induced dopamine surges
and subsequent striatal neuronal activity are critical for
maintaining a willingness to exercise. The activation of
dopamine signaling restored the exercise performance of
antibiotic-treated mice, as the authors have noted. Fur-
thermore, the authors have indicated that the expression
of the dopamine-degrading enzyme, MAO, decreased in
the exercising mice, but not in those where the micro-
biota was depleted, indicating that the latter’s sluggish
dopamine response was due to MAO-driven dopamine
turnover. Restoration of the gut microbiome, inhibition
of MAO, and increased artificial dopamine signaling in
the striatum are adequate measures for reinstating exer-
cise capacity in mice that lack gut bacteria. Additionally,
the microbiota’s influence on dopamine signaling requires
SUN et al.
the involvement of intestinal neurosensory neurons that
expressed TRPV1 and CB1. Most importantly, the authors
have demonstrated that microbiota-derived FAAs promote
exercise-induced neuronal activation, striatal dopamine
release, and enhance motor performance.
In conclusion, the work by Dohnalová et al.1 has
important implications for our understanding of exercise
physiology and the relationship between the gut micro-
biota and exercise behavior. By uncovering a potential
mechanism by which the gut microbiota enhances the
body’s desire to exercise, this study opens up new avenues
for research into the gut–brain axis and exercise. Further-
more, the finding that the gut microbiota also influences
the “Runner’s High” phenomenon through the release of
endocannabinoids, which were known to have analgesic
properties, provide insights into how the gut microbiota
and peripheral CB1 signaling can regulate pain sensitiv-
ity during exercise. This gut-to-brain pathway may have
evolved to link nutrient availability and the state of the gut
bacterial population with readiness for prolonged exercise.
Nevertheless, certain crucial matters are yet to be resolved,
such as the signaling mechanism originating from sensory
neurons that govern the expression of MAO in the stria-
tum. The discoveries made by the authors allude to fresh
insights concerning the factors that may augment physi-
cal prowess. Should these revelations be substantiated in
humans, they prompt the inquiry of whether manipulat-
ing gut microbiota or adhering to certain dietary regimens
could ameliorate cognitive functions linked to exercise in
a personalized manner.
AU T H O R CO N T R I B U T I O N S
Wenhuan Sun drew the images and wrote the article. Fang-
fang Zhou and Zhenjiang Bai provided modifications. All
authors have read and approved the final manuscript.
3 of 3
AC K N OW L E D G M E N T S
The current work was supported by the National Natu-
ral Science Foundation of China (NSFC) (grant number:
U20A20393) and the National Science Fund for Distin-
guished Young Scholars (grant numbers: 32125016).
C O N F L I C T O F I N T E R E S T S TAT E M E N T
The authors declare they have no conflicts of interest.
D A T A AVA I L A B I L I T Y S T A T E M E N T
No data was used for the research described in this
highlight.
E T H I C S S TAT E M E N T
No ethical approval was necessary for this work.
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How to cite this article: Sun W, Bai Z, Zhou F.
The microbiota–gut–brain axis regulates
motivation for exercise. MedComm. 2023;4:e304.
https://doi.org/10.1002/mco2.304