Relationship between the gut microbiome and measures of aerobic fitness in humans

Exercise training appears to increase diversity and abundance of certain taxa in the human gut microbiome. Further, results from animal models suggest gut microbes stimulate muscle mitochondrial adaptations (mitohormesis) through an unknown mechanism. Our goal was to describe gut microbiome composition in relation to fitness in both men and women. We further aimed to explore the hypothesis that gut microbiomes confer metabolic fitness through their stimulation of host cell mitochondrial adaptations in humans. We hypothesize that fitness will be correlated with both an increase in gut microbiome diversity and mitohormetic activity in men and women. METHODS: Twenty-seven healthy participants (men n=12, women n=15) were categorized for fitness based on maximal oxygen uptake (VO 2 MAX), determined from a graded exercise test on a cycle ergometer, and maximal metabolic steady state (MMSS), as predicted from muscle oxygen saturation measured via NIRS. Participants also provided a fecal sample within 48 hours of the MMSS protocol. Fecal microbiome composition was determined by 16S ribosomal RNA gene amplicons and metagenomic sequence analysis. Microbiome alpha diversity (Shannon Index) and beta diversity (Bray-Curtis analysis) were compared to fitness metrics. Fecal microbiome-derived mitohormetic activity was determined by incubating C2C12 myotubes with participant fecal extracts and measuring myotube citrate synthase activity. RESULTS: Fitness, defined by peak power and VO 2 MAX, accounted for 7% of the variance in beta diversity (PERMANOVA: F = 1.89, p = 0.022). Alpha diversity was positively correlated to VO 2 MAX (R = 0.22, p = 0.26) and MMSS (R = 0.3, p = 0.13). Alpha diversity in men was highly correlated to absolute VO 2 MAX (R = 0.62, p = 0.037) and MMSS (R = 0.72, p = 0.011), whereas no correlation was found between alpha diversity and VO 2 MAX (R = 0.064, p = 0.82) nor MMSS (R = 0.089, p = 0.75) in women. There was a positive correlation between participants’ VO 2 MAX (L/min) and citrate synthase activity elicited in C2C12 myotubes by their fecal extracts (r = 0.41, p = 0.03). CONCLUSIONS: Results indicate an important sex difference in gut microbiome alpha diversity as it relates to fitness, where men demonstrate a clear correlation between alpha diversity and fitness while women did not. Some unknown substances in fecal extracts appear to drive mitochondrial adaptations in C2C12 myotubes in a fitness-dependent manner. Funding: Wu Tsai Human Performance Alliance at the University of Oregon This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.