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

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.

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.

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.

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.

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.