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A microbiome-dependent gut brain pathway regulates motivation for exercise

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mouse

SUBMITTER: ANDREW DAVID Patterson

PROVIDER: MSV000091494 | MassIVE | Wed Mar 15 13:28:00 GMT 2023

REPOSITORIES: MassIVE

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

Dohnalová Lenka L Lundgren Patrick P Carty Jamie R E JRE Goldstein Nitsan N Wenski Sebastian L SL Nanudorn Pakjira P Thiengmag Sirinthra S Huang Kuei-Pin KP Litichevskiy Lev L Descamps Hélène C HC Chellappa Karthikeyani K Glassman Ana A Kessler Susanne S Kim Jihee J Cox Timothy O TO Dmitrieva-Posocco Oxana O Wong Andrea C AC Allman Erik L EL Ghosh Soumita S Sharma Nitika N Sengupta Kasturi K Cornes Belinda B Dean Nitai N Churchill Gary A GA Khurana Tejvir S TS Sellmyer Mark A MA FitzGerald Garret A GA Patterson Andrew D AD Baur Joseph A JA Alhadeff Amber L AL Helfrich Eric J N EJN Levy Maayan M Betley J Nicholas JN Thaiss Christoph A CA

Nature 20221214 7941

Exercise exerts a wide range of beneficial effects for healthy physiology<sup>1</sup>. 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 con ...[more]

PMID: 36517598

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