The Gut–Muscle–Immune Axis in Motion: Mechanistic Synergies of SCFA Metabolism, Exercise, and Microbial Cross-Feeding

BACKGROUND: The gut microbiota plays a fundamental role in metabolic and immune homeostasis through the production of short-chain fatty acids (SCFAs). These metabolites influence mitochondrial biogenesis, muscle energetics, epithelial barrier stability, and inflammatory regulation via G-protein-coupled receptors, AMPK-PGC-1α signaling, and epigenetic remodeling. OBJECTIVE: This review synthesizes current evidence on the gut-muscle-immune axis, emphasizing how dietary fermentable substrates, microbial cross-feeding interactions, and structured exercise modulate SCFA production and shape host physiological adaptation. METHODS: We integrated findings from human and animal studies, multi-omic analyses, metabolomic and microbiome research, and exercise physiology to outline mechanistic links between microbial metabolism and systemic resilience. RESULTS: Key mechanistic pathways connecting dietary fiber fermentation to mitochondrial function, redox regulation, immune homeostasis, and metabolic plasticity are summarized. We further present the Targeted Gut Protocol 2.0, a conceptual 12-week framework combining fiber-diversity targets, lactate-guided exercise periodization, biomarker monitoring, and adaptive feedback mechanisms to enhance endogenous SCFA availability. CONCLUSIONS: SCFA-driven metabolic plasticity provides an integrative model through which lifestyle behaviors can modulate host physiology. Future research should prioritize standardized sampling approaches, causal inference methods, multi-omic integration, and AI-supported personalization to refine mechanistic understanding and strengthen translational potential.