The Short-Term Influence of Antibiotics on the Gut Microbiome & Exercise Capacity

Background: Preclinical animal models demonstrate that antibiotic-induced gut microbiota depletion impairs endurance exercise capacity, yet translational evidence in healthy human cohorts remains scarce. Objective: This study evaluated the short-term influence of a 5-day course of azithromycin (AZN) on gut microbial diversity, treadmill exercise performance, and the serum metabolome in healthy, physically active adults. Methods: In a double-blind, randomized, placebo-controlled trial, 31 recreationally active young adults (18 males, 13 females) received either AZN (500 mg on day 1, 250 mg·d⁻¹ on days 2–5) or an inert placebo. Pre- and post-intervention evaluations included fecal 16S rRNA gene sequencing (V4 region), submaximal running and heart rate economy, rating of perceived exertion, a 5 km treadmill time trial, and serum liquid chromatography mass spectroscopy (LC-MS) targeted metabolomics. Results: AZN treatment reduced gut microbial alpha diversity (observed ASVs, Shannon index, and Faith's phylogenetic diversity; p < 0.05) and qualitative beta diversity (Jaccard and unweighted UniFrac distances; P < 0.05) based on post-treatment group differences. In contrast, community evenness and quantitative, abundance-weighted beta diversity metrics (weighted UniFrac and Bray-Curtis) were not significantly altered. Despite pronounced microbial dysbiosis, AZN caused no significant changes in body composition, running economy, heart rate economy, rating of perceived exertion, or 5 km time trial performance. Systemic serum metabolomics revealed significant post-treatment reductions in amino acids, including branched-chain amino acids (leucine, isoleucine, valine), lysine, arginine, tryptophan, and tyrosine (P < 0.05). Conclusion: Short-term broad-spectrum azithromycin administration induced qualitative gut dysbiosis and altered some circulating amino acid pools without acutely compromising 5 km running performance in active adults. This provides preliminary evidence demonstrating host physiological resilience to transient microbial perturbation.