Microbiota-Derived Metabolites in the Epigenetic Regulation of Redox Homeostasis

Redox homeostasis is essential for intestinal and systemic health and is regulated by antioxidant defense systems and redox-sensitive signaling pathways such as the nuclear factor erythroid 2-related factor 2 (Nrf2) and the nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-κB). Disturbances in this balance promote oxidative stress, chronic inflammation, and disease progression. Increasing evidence indicates that microbiota-derived metabolites act as key modulators of redox biology by shaping host gene expression through receptor-mediated signaling, metabolic regulation, and chromatin-associated mechanisms, including histone modifications, DNA methylation, and changes in chromatin accessibility. This review discusses how major classes of microbiota-derived and microbiota-modulated metabolites, including short-chain fatty acids (SCFAs), secondary bile acids, tryptophan-derived metabolites, polyphenol metabolites, hydrogen sulfide, and lipid mediators, influence redox-sensitive signaling and epigenetic regulation. We highlight their effects on intestinal barrier integrity and immune cell function, with particular emphasis on macrophage polarization and T-cell differentiation. Finally, we consider the emerging translational relevance of the microbiota-metabolite-epigenetic axis, while emphasizing that biomarker development and therapeutic applications require further mechanistic validation and clinical studies.