Gut microbes influence the motivation to exercise

A recent article published in Nature by a group of researchers from the Perelman School of Medicine at the University of Pennsylvania revealed a gut–brain connection that explains why certain gut microbes influence the motivation to exercise and enhance exercise performance. It’s no secret that exercise has a wide range of beneficial effects on one’s physiology. But why exactly do we want to hit the treadmill, i.e., the motivation to exercise, is much less understood. In this study, the researchers reported the discovery of a gut–brain pathway in mice that enhances exercise performance by increasing the levels of dopamine released during physical activity. The authors concluded that stimulation of this gut-brain pathway improves exercise performance whereas microbiome depletion causes the opposite. In other words, it was demonstrated that exercise performance is, at least partially, microbiome-dependent. The results also suggest that certain bacterial metabolites that help deliver signals from the gut to the brain may enhance the motivation to exercise itself (Figure 1).

Figure 1. The impact of the intestinal microbiome on exercise performance in mice.

In the present study, the authors found that certain microorganisms living in the gut boost running performance in mice. These microbes produce metabolites that stimulate sensory nerves in the gut which, in turn, increase activity in the brain region that controls exercise motivation.

Exercise performance is, at least partially, microbiome-dependent

To search for factors affecting exercise performance, the researchers used almost 200 genetically distinct, previously untrained mice. They deeply investigated all of these mice and collected different types of biological and chemical information. Analyses and methods that were used in this study included, among others, 16S ribosomal DNA sequencing from the stool samples, multiparameter metabolic analysis, genomic analysis, and serum metabolomics. These analyses resulted in over 10,000 data points per mouse. Then, the researchers created exercise profiles for the mice that either voluntarily ran on wheels or underwent endurance running on treadmills. These exercise profiles revealed significant variability between animals in both wheel and treadmill running. Subsequently, the researchers used a machine-learning approach using all the collected data points to identify variables that could best explain differences in the exercise performance.

After studying the mice’s genomes, it was concluded that the genetics of the mice themselves played a very minor role in exercise performance. Subsequent analysis of non-genetic parameters, including serum metabolites, gut microbiome composition, and metabolic parameters revealed that differences in gut bacterial populations accounted for a substantial portion of performance variability. More detailed analysis of the gut microbiome allowed them to identify two bacterial species whose presence was closely linked with better exercise performance. A member of the Erysipelotrichaceae family (Eubacterium rectale) and a member of the Lachnospiraceae family (Coprococcus eutactus) significantly enhanced exercise performance compared to germ-free mice. These data demonstrate the causal relationship between the gut microbiome and exercise performance, meaning that certain gut bacteria influence results of a physical activity.

The data demonstrate that some species of gut bacteria influence results of a physical activity.

The next step was to determine how exactly the gut microbiome affects exercise performance which was achieved by performing untargeted metabolomics and correlating the results with exercise parameters. This analysis revealed that numerous fatty acid amides (FAAs), such as N-oleoylethanolamide (OEA), were among the most potent metabolites that stimulate sensory neurons. OAE concentration was significantly lower after application of antibiotics that impaired exercise performance and correlated with wheel running results suggesting that intestinal FAA metabolites may stimulate sensory neurons to enhance the motivation for exercise.

How do they do that? Further results showed that FAA metabolites stimulate the endocannabinoid receptor CB1. CB1-expressing sensory neurons then send an exercise-induced signal to the brain region involved in motivated behavior and the initiation of physical activity, striatum. This signal sent to striatum contributes to higher levels of dopamine and enhances exercise capability.

Overall, these results suggest the possibility to design affordable diet-based tools that would increase the performance in professional athletes and motivate the general public to start exercising or to exercise more. In addition, it is also possible that a better understanding of this gut-brain connection may help increase motivation in subjects suffering from addiction or depression. Another interesting piece of evidence points to the fact that better-performing mice were less sensitive to pain and had a more significant so-called "runner's high" (the phenomenon of pleasure and reward that is driven by endocannabinoid release after prolonged physical activity), suggesting that this euphoric sensation after exercising might also be partly controlled by gut microbes. The next logical step is to try finding a similar gut-to-brain pathway in humans, exactly what the team is planning on doing next.

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Reference:

Dohnalová, L., Lundgren, P., Carty, J.R.E. et al. A microbiome-dependent gut–brain pathway regulates motivation for exercise. Nature 612, 739–747 (2022). https://doi.org/10.1038/s41586-022-05525-z