In Nature, researchers at the University of Pennsylvania, Goethe University Frankfurt, and elsewhere consider gut microbiome contributions to exercise motivation and corresponding exercise-induced changes to the brain's neurochemistry. Based on a series of genotyping, serum metabolomics, RNA sequencing, and 16S ribosomal RNA gene sequencing on stool samples from 199 outbred mice, the team suggests that endocannabinoid metabolites produced by gut microbes can influence TRPV1-expressing sensory neurons in the brain by enhancing exercise-related dopamine neurotransmitter signaling. "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," the authors write. "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.