Two Gut Bacteria Linked to Exercise Motivation in Mice

Researchers from University of Pennsylvania’s Perelman School of Medicine report evidence that certain species of gut-dwelling bacteria activate nerves in the gut that promote the desire to exercise.

Published in a recent issue of Nature, the mouse study found that differences in running performance within a large group of lab mice were largely attributable to the presence of certain gut bacterial species in the higher-performing animals. The researchers traced this effect to small molecules called metabolites that the bacteria produce—metabolites that stimulate sensory nerves in the gut to enhance activity in a motivation-controlling brain region during exercise.

“If we can confirm the presence of a similar pathway in humans, it could offer an effective way to boost people’s levels of exercise to improve public health generally,” says study senior author Christoph Thaiss, PhD, an assistant professor of Microbiology at Penn Medicine.

The study, published recently in Nature, was designed to search broadly for factors that determine exercise performance. Thaiss and colleagues recorded the genome sequences, gut bacterial species, bloodstream metabolites, and other data for genetically diverse mice. They then measured the amount of daily voluntary wheel running the animals did, as well as their endurance.

The researchers analyzed these data using machine learning, seeking attributes of the mice that could best explain the animals’ sizeable inter-individual differences in running performance. They were surprised to find that genetics seemed to account for only a small portion of these performance differences—whereas differences in gut bacterial populations appeared to be substantially more important. In fact, they observed that giving mice broad-spectrum antibiotics to get rid of their gut bacteria reduced the mice’s running performance by about half.

Ultimately, in a years-long process involving more than a dozen separate laboratories at Penn and elsewhere, the researchers found that two bacterial species closely tied to better performance, Eubacterium rectale and Coprococcus eutactus, produce metabolites known as fatty acid amides (FAAs). The latter stimulate receptors called CB1 endocannabinoid receptors on gut-embedded sensory nerves, which connect to the brain via the spine. The stimulation of these CB1 receptor-studded nerves causes an increase in levels of the neurotransmitter dopamine during exercise, in a brain region called the ventral striatum.

The striatum is a critical node in the brain’s reward and motivation network. The researchers concluded that the extra dopamine in this region during exercise boosts performance by reinforcing the desire to exercise.

“This gut-to-brain motivation pathway might have evolved to connect nutrient availability and the state of the gut bacterial population to the readiness to engage in prolonged physical activity,” says study co-author, J. Nicholas Betley, PhD, an associate professor of Biology at the University of Pennsylvania’s School of Arts and Sciences. “This line of research could develop into a whole new branch of exercise physiology.”

There was also evidence from the experiments that the better-performing mice experienced a more intense “runner’s high”—measured in this case by a reduction in pain sensitivity—hinting that this phenomenon is also at least partly controlled by gut bacteria.

The team now plans further studies to confirm the existence of this gut-to-brain pathway in humans, which could lead to a safe, diet-based method of getting ordinary people running and optimizing elite athletes’ performance. The findings could also yield easier methods for modifying motivation and mood in settings such as addiction and depression.