Human exercise motivational states are controlled by microbiome

By: Evelyn Nguyen

Evolutionary biologists firmly believe that modern humans thrive out of Darwinian evolution because our ancestors possessed superior locomotive ability. The typical modern lifestyle of reduced bipedal movement, therefore unsurprisingly, has been identified as a risk factor for modern-day noncommunicable diseases such as metabolic, neurological and neoplastic conditions. As a result, targeted efforts to reverse this trend are vital and exercise has been mentioned countlessly as one of the most effective methods. The integrative biology of exercise is commonly referred to as a complex orchestra of whole-body homeostatic changes due to a significant increase in musculoskeletal contraction and energy demand, adaptations occur across the body including the musculoskeletal system, cardiovascular, respiratory and motivational aspects. In recent years, numerous excellent reviews have described skeletal muscle adaptation, however, the mechanism underlying motivation for exercise is still lacking. In the article by …, the authors conducted experiments and discovered a gut-brain pathway exercise enhancement pathway mediating through the neurotransmitter dopamine.

Mice were tested for endurance using treadmill exercise and exhaustion using voluntary running on wheels. To determine how much intestinal microbiome composition accounts for the resulting variability, a loss-of-function and gain-of-function experiment was conducted. Loss-of-function mice illustrated worse exercise performance on both running wheels and treadmills. Gain-of-function was done through the transfer of microbiome samples from the original diversity of outbred mice to germ-free mice. Consistent with loss-of-function, a strong correlation between exercise performance was seen between donors and recipients. Next, to narrow down the specific microbiome taxonomic, different specific antibiotics combination was used. The exercise capability for both treadmill and wheel settings decline across all antibiotics, except for neomycin. 16S DNA profiling was conducted between mice with the most differences, neomycin-treated and ampicillin-treated. Members of Erysipelotrichaceae and Lachnospiracaea families were nominated as possible drivers of exercise performance difference seen. To confirm the contribution of each species, mono-colonisation and subsequent 16 quantitative PCR and sequencing was done. Eubacterium and Coproccocus positively impacted exercise performance compared to germ-free mice, reaching equivalent levels to conventionally bred. As a result, a causal relationship between microbiome performance was established.

The main brain region associated with motivation is the striatum. To determine whether gut microbiome affects striatal response, single-nucleus RNA sequencing was conducted on pre-exercise and post-exercise antibiotic-treated mice. Results indicated that regulator genes for medium spiny neurons, Arc and Fos, decreased in microbiome absence mice. Since dopamine controls the medium spiny neurons, levels of dopamine in antibiotics-treated mice were recorded. Unexpectedly, the usual rise in dopamine levels post-exercise was not seen in microbiome-depleted populations. This emphasised the importance of exercise-induced striatal response. Microbiome was then transplanted to germ-free mice to evaluate whether exercise-triggered dopamine rises mechanistically acted to result in performance stimulating effect of the microbiome. Speculation was proven correct when the rise in dopamine levels was observed in transplanted mice. To establish the mechanism of how gut microbiome depletion impaired exercise-induced dopamine levels in the striatum, the turnover rate of dopamine was investigated. The level of monoamine oxidase enzyme (MAO) was higher in germ-free mice compared to those conventionally bred. Therefore, it can be concluded that the intestinal microbiome regulates the striatal dopamine level by mediating the levels of MAO-driven dopamine turnover.

In conclusion, the gut microbiome is involved in the motivational state of exercise through dopamine level regulation mediated by the MAO enzyme.


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