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Guts to Run—How the Microbiome Motivates Exercise

Scientists discovered a novel way the gut signals to the brain to influence motivation to exercise in mice. The importance of physical activity to health is well known, but participating in exercise can be challenging for many, and motivation to start or continue physical activity varies among people. Understanding the factors that drive exercise is critical to developing strategies to help people start and maintain motivation for physical activity.

To discover new regulators of exercise, researchers undertook a systematic approach and documented the genome, metabolome (products of metabolism), intestinal microbiome (the microbes inhabiting the gut), energy metabolism, and exercise profiles of approximately 200 genetically diverse male and female mice to produce over 2 million data points. Because the scientists observed significant variability in the exercise performance of the mice in both treadmill and wheel running, they applied machine-learning techniques to identify factors that correlated with either enhanced or decreased performance. These studies led to a surprising observation: the presence or absence of specific bacteria in the gut microbiome of the mice had a strong predictive power on the mice’s exercise performance. Further experiments demonstrated that removal of the microbiome by treatment with antibiotics decreased exercise performance, while reconstituting the microbiome by transplantation or stopping the antibiotic treatment restored performance. This suggested that the microbiome contributed to exercise performance in a specific, acute, and reversible way.

Through an impressive body of work, the scientists revealed that gut microbiome production of metabolites—specifically fatty acid amides—promoted exercise in the mice. These metabolites stimulated gut sensory neurons which, in return, signaled to neurons in a specific part of the brain responsible for motivation. This signal enhanced levels of dopamine, a key molecule in the brain that—among other functions—promotes the feeling of reward. In microbiome-depleted mice, levels of dopamine post-exercise were reduced, leading the mice to exercise less. In contrast, activation of dopamine signaling in these mice restored motivation to exercise even in the absence of a gut microbiome.

This surprising discovery showed that brain activity contributing to exercise motivation is influenced by the gut microbiome, a previously unknown gut-brain connection affecting behavior. Additional research is necessary to determine whether a similar gut- brain connection exists in humans, but this research could spur exciting new strategies to modify behavior through lifestyle interventions, diet, and metabolite supplementation, to help people live healthier lives.

Dohnalová L, Lundgren P, Carty JRE,…Thaiss CA. A microbiome-dependent gut-brain pathway regulates motivation for exercise. Nature 612: 739- 747, 2022.
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