Exercise, physical activity and a healthy diet are the hallmarks of the prevention of most non-communicable diseases. The same holds true for cardiovascular disease prevention. Many large-scale epidemiological studies, randomised controlled clinical trials and animal models have shown that regular physical activity and/or exercise can reduce the burden of cardiovascular disease. Hence, the current ESC(1) and AHA guidelines recommend that individuals should aim for a physically active lifestyle for primary and secondary cardiovascular disease prevention. Yet, one problem remains: adherence to sufficient levels of physical activity remains low.
In a recent study by Dohnalová et al. published in Nature in December 2022(2), the authors aimed to improve our understanding of what determines the motivation to be physically active. In their study, the authors measured the exercise performance of deeply profiled, genetically and metagenomically diverse outbred mice. Overall, a cohort of 199 diversity-outbred mice strains were used. These mice were derived from eight defined intercrossed genetic backgrounds. For each mouse, an astonishing number of 10,500 data points including information on single nucleotide polymorphisms, serum metabolomics, 16S ribosomal DNA sequencing of stool samples were available.
In a first step, the genetic factors underlying voluntary physical activity were explored. Interestingly, here the narrow-sense heritability (i.e. the fraction of the running performance that can be attributed to variation in the additive effects of genes) was rather low, which agrees with previous twin-studies in humans.
In a second step, a machine-learning algorithm (gradient-boosting decision tree) was used with all other available features (i.e. serum metabolomics, intestinal microbiome composition and metabolic parameters) to predict running performance. The authors report that the effect of the microbiome was similar to those of serum metabolome and all measured parameters together. To determine whether the observed associations were causal, the authors used loss of function (microbiome depletion) and gain of function (microbiome transplantation) experiments. Here a strong functional contribution of the microbiome to exercise capacity was confirmed. The authors demonstrated that broad-spectrum antibiotics reduced exercise performance in both sexes and this effect was reversible. Further, home cage and open field locomotion was not impacted.
In a next step, the mice were fed with the antibiotics neomycin or ampillicin to identify which specific taxonomic elements of the microbiome are necessary for exercise performance. Here a member of the gut bacteria Lachnospiraceae (Coprococcus eutactus) and the Erysipelotrichaceae (Eubacterium rectale) families enhanced exercise performance.
Now how does the microbiome influences exercise behavior? Previous studies have reported a relationship between muscle function and microbiome. A second possibility is the brain which influences motivation. In a very elegant set of experiments, the authors show that the intestinal microbiome is important for the exercise-triggered activation of the striatum. Since the striatal medium spiny neurons are largely controlled by dopamine, the effect of the microbiome on dopamine levels was assessed. The microbiome was necessary for a full dopamine response to acute exercise. The authors used denervated gut-innervating afferent sensory neurons to determine the role their role in signal transduction. The authors saw that the spinal pathway was more sensitive to microbiome-derived signals and also showed that TRPV1+ neurons are required for exercise performance. In a next step the authors tested which metabolites of the microbiome could activate dorsal root ganglion neurons. The most potent metabolites included fatty acid amides (e.g. oleoylethanolamide). When fatty acid amides were provided by supplement or by gastric infusion, a role of intestinal fatty acid amines was confirmed.
Overall, this amazing paper shows that the gut microbiome supports that synthesis of intestinal free fatty amines to activate endocannabinoid receptor CB1-expressing TRPV1+ sensory neurons, which send an exercise-induced afferent signal to the brain to downregulate the abundance of monoamine oxidase in the striatum. A lower monoamine oxidase induces greater levels of dopamine and enhances exercise capability. Since the gut microbiome is largely dependent on what one eats, one could even speculate that, given the findings of this study, certain supplements or nutritional interventions could be used to increase to desire for a physically active lifestyle and thereby reduce the burden of sedentarism with regards to cardiovascular disease.
Our mission: To reduce the burden of cardiovascular disease.