A microbiome-dependent gut-brain pathway regulates motivation for exercise.

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JMG, Animals, Mice, Brain, Dopamine, Endocannabinoids, Motivation, Sensory Receptor Cells, Brain-Gut Axis, Gastrointestinal Microbiome, Exercise, Physical Conditioning, Animal, Models, Animal, Humans, Ventral Striatum, Running, Reward, Individuality

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Nature. 2022;612(7941):739-47.





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P.L. was supported by the NIH (F31HL160065), N.G. by NSF GFRP (DGE-1845298) and J.K. by a Boehringer Ingelheim MD Fellowship. A.D.P. was supported by NIH grant no. S10-OD021750. J.N.B. is supported by NIH grant no. P01DK119130 and R01DK115578, and by a Klingenstein-Simons Fellowship. C.A.T. is a Pew Biomedical Scholar and a Kathryn W. Davis Aging Brain Scholar and is supported by the NIH Director’s New Innovator Award (grant no. DP2AG067492), NIH grant no. R01-DK-129691, the Edward Mallinckrodt, Jr Foundation, the Agilent Early Career Professor Award, the Global Probiotics Council, the Mouse Microbiome Metabolic Research Program of the National Mouse Metabolic Phenotyping Centers and grants by the IDSA Foundation, the Thyssen Foundation, the Human Frontier Science Program (HFSP), the Penn Center for Musculoskeletal Disorders (grant no. P30-AR-069619), the PennCHOP Microbiome Program, the Penn Institute for Immunology, the Penn Center for Molecular Studies in Digestive and Liver Diseases (grant no. P30-DK-050306), the Penn Skin Biology and Diseases Resource-based Center (grant no. P30-AR-069589), the Penn Diabetes Research Center (grant no. P30-DK-019525), the Penn Institute on Aging and the Dean’s Innovation Fund of the University of Pennsylvania Perelman School of Medicine.


Exercise exerts a wide range of beneficial effects for healthy physiology. However, the mechanisms regulating an individual’s motivation to engage in physical activity remain incompletely understood. An important factor stimulating the engagement in both competitive and recreational exercise is the motivating pleasure derived from prolonged physical activity, which is triggered by exercise-induced neurochemical changes in the brain. Here, we report on the discovery of a gut–brain connection in mice that enhances exercise performance by augmenting dopamine signalling during physical activity. We find that microbiome-dependent production of endocannabinoid metabolites in the gut stimulates the activity of TRPV1-expressing sensory neurons and thereby elevates dopamine levels in the ventral striatum during exercise. Stimulation of this pathway improves running performance, whereas microbiome depletion, peripheral endocannabinoid receptor inhibition, ablation of spinal afferent neurons or dopamine blockade abrogate exercise capacity. These findings indicate that the rewarding properties of exercise are influenced by gut-derived interoceptive circuits and provide a microbiome-dependent explanation for interindividual variability in exercise performance. Our study also suggests that interoceptomimetic molecules that stimulate the transmission of gut-derived signals to the brain may enhance the motivation for exercise.