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

Lenka Dohnalová, Patrick Lundgren, Jamie R. E. Carty, Nitsan Goldstein, Sebastian L. Wenski, Pakjira Nanudorn, Sirinthra Thiengmag, Kuei-Pin Huang, Lev Litichevskiy, Hélène C. Descamps, Karthikeyani Chellappa, Ana Glassman, Susanne Kessler, Jihee Kim, Timothy O. Cox, Oxana Dmitrieva-Posocco, Andrea C. Wong, Erik L. Allman, Soumita Ghosh, Nitika Sharma, Kasturi Sengupta, Belinda Cornes, Nitai Dean, Gary A. Churchill, Tejvir S. Khurana, Mark A. Sellmyer, Garret A. FitzGerald, Andrew D. Patterson, Joseph A. Baur, Amber L. Alhadeff, Eric J. N. Helfrich, Maayan Levy, J. Nicholas Betley and Christoph A. Thaiss ()
Additional contact information
Lenka Dohnalová: University of Pennsylvania
Patrick Lundgren: University of Pennsylvania
Jamie R. E. Carty: University of Pennsylvania
Nitsan Goldstein: University of Pennsylvania
Sebastian L. Wenski: Goethe University Frankfurt, and LOEWE Center for Translational Biodiversity Genomics
Pakjira Nanudorn: Goethe University Frankfurt, and LOEWE Center for Translational Biodiversity Genomics
Sirinthra Thiengmag: Goethe University Frankfurt, and LOEWE Center for Translational Biodiversity Genomics
Kuei-Pin Huang: Monell Chemical Senses Center
Lev Litichevskiy: University of Pennsylvania
Hélène C. Descamps: University of Pennsylvania
Karthikeyani Chellappa: University of Pennsylvania
Ana Glassman: University of Pennsylvania
Susanne Kessler: University of Pennsylvania
Jihee Kim: University of Pennsylvania
Timothy O. Cox: University of Pennsylvania
Oxana Dmitrieva-Posocco: University of Pennsylvania
Andrea C. Wong: University of Pennsylvania
Erik L. Allman: the Pennsylvania State University
Soumita Ghosh: University of Pennsylvania
Nitika Sharma: University of Pennsylvania
Kasturi Sengupta: University of Pennsylvania
Belinda Cornes: The Jackson Laboratory
Nitai Dean: Hoss Technology
Gary A. Churchill: The Jackson Laboratory
Tejvir S. Khurana: University of Pennsylvania
Mark A. Sellmyer: University of Pennsylvania
Garret A. FitzGerald: University of Pennsylvania
Andrew D. Patterson: the Pennsylvania State University
Joseph A. Baur: University of Pennsylvania
Amber L. Alhadeff: Monell Chemical Senses Center
Eric J. N. Helfrich: Goethe University Frankfurt, and LOEWE Center for Translational Biodiversity Genomics
Maayan Levy: University of Pennsylvania
J. Nicholas Betley: University of Pennsylvania
Christoph A. Thaiss: University of Pennsylvania

Nature, 2022, vol. 612, issue 7941, 739-747

Abstract: Abstract Exercise exerts a wide range of beneficial effects for healthy physiology1. 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.

Date: 2022
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DOI: 10.1038/s41586-022-05525-z

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