A study led by researchers at the University of Pennsylvania Perelman School of Medicine has found that some species of gut-dwelling bacteria activate nerves in the gut to promote the desire to exercise. The research 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 team then traced this effect to bacterially produced metabolites activating sensory nerves in the gut to stimulate a motivation-controlling brain region, which then promotes the desire to 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,” said Christoph Thaiss, PhD, an assistant professor of Microbiology at Penn Medicine. Apart from the potential to develop inexpensive, safe, diet-based ways of getting ordinary people out running, and possibly even optimizing elite athletes’ performance, the newly discovered pathway offer up insights that point to new strategies for modifying motivation and mood in settings such as addiction and depression.

Thaiss is senior author of the team’s published paper in Nature, which is titled “A microbiome-dependent gut-brain pathway regulates motivation for exercise,” in which the researchers say that their findings suggest “… a possible mechanistic basis for understanding interindividual variability to exercise motivation and performance.”

Exercise is possibly the single most important and accessible lifestyle component that offers protection from a large range of diseases, the authors wrote. “But exercise is strenuous and requires, in addition to cardiovascular and respiratory fitness, a strong motivational state in professional, recreational or therapeutic settings alike.” One important factor in stimulating engagement—whether for competitive or recreational exercise—is the motivating pleasure that is derived from prolonged physical activity, and which is triggered by exercise-induced neurochemical changes in the brain. But as the team also noted, “… the mechanisms regulating an individual’s motivation to engage in physical activity remain incompletely understood.”

Thaiss and colleagues set up their study to search broadly for factors that might determine exercise performance. They recorded the genome sequences, gut bacterial species, bloodstream metabolites, and other data for a cohort of 199 genetically diverse mice. “We deeply profiled this cohort by single nucleotide polymorphism genotyping, serum metabolomics, 16S ribosomal DNA (rDNA) sequencing of stool samples and multiparameter metabolic analysis,” they wrote. The analysis resulted in more than 10,500 collected data points per mouse, and close to 2.1 million data points in total. The investigators 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, to look for 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—“the genetic contribution to interindividual variability in exercise capacity was minor” they noted in their report—whereas differences in gut bacterial populations appeared to be substantially more important. In fact, the scientists found that giving mice broad-spectrum antibiotics to deplete their gut bacteria reduced the animals’ running performance by about half. “Microbiome ablation by broad-spectrum antibiotics reduced both treadmill and running wheel performance by about 50%,” the scientists wrote.

Following continued detective research involving more than a dozen separate laboratories at Penn and elsewhere, over a number of years, the team found two bacterial species closely tied to better performance, Eubacterium rectale and Coprococcus eutactus, produce fatty acid amides (FAAs), which stimulate receptors called CB1 endocannabinoid receptors on gut-embedded sensory nerves that connect to the brain via the spine. The research indicated that 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, the team pointed out, “a brain region critically involved in motivated behavior and the initiation of physical activity …” They concluded that the extra dopamine in this region during exercise boosts performance by reinforcing the desire to exercise. “In this study, we demonstrate that the brain circuitry involved in regulating the motivation for physical activity is not strictly central nervous system autonomous but is shaped by peripheral influences that originate in the intestinal microbial community, suggesting a possible mechanistic basis for understanding interindividual variability in exercise motivation and performance,” they stated.

“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,” said 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.”

The findings open up many new avenues of scientific investigation. For example, there was 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 well-known phenomenon is also at least partly controlled by gut bacteria. The results, they noted, “… suggest that the neurochemical effects underlying the ‘runner’s high’, the phenomenon of pleasure, reward, anxiolysis and analgesia that is driven by endocannabinoid release after prolonged physical activity, might be influenced by the gastrointestinal tract.”

Also, the team pointed out, the findings may suggest that other behaviors that are dependent on striatal dopamine signaling could potentially be modifiable through lifestyle interventions, diet or through metabolite supplementation. This they added, could open up the more general concept of “interoceptomimetics,” or molecules that stimulate these sensory pathways and influence brain activity through peripheral intervention. The team now plans further studies to confirm the existence of this gut-to-brain pathway in humans. “If applicable to humans, our findings imply that interoceptomimetics that stimulate the motivation for exercise might present a powerful opportunity to counteract the detrimental health impact of a sedentary lifestyle,” they concluded.