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, The Jackson Laboratory
Nitai Dean
Gary Churchill, The Jackson Laboratory
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
Christoph A Thaiss


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.