Microbiota-driven epigenetic programming of local immunity.

The maintenance of local immunity requires stable tissue adaptation, implying that persistent environmental cues must continuously reinforce niche-specific immune programs. Microbiota-derived metabolites are increasingly recognized as such cues, acting not merely as metabolic byproducts but as epigenetic inputs that regulate histone modifications, DNA and histone methylation, and non-coding RNA networks. Through these epigenetic mechanisms, microbial metabolites reprogram key immune populations by promoting tolerogenic or immunostimulatory states, tuning effector and memory differentiation, and reshaping subset-specific functions in a tissue-dependent manner. Tissue-level studies have further shown that this microbiota-epigenome crosstalk influences barrier tolerance in the gut and skin, antiviral and inflammatory responses in the lung, metabolic and fibrogenic programs in the liver, and microglial immune tone in the brain. However, studies establishing a complete causal chain from a defined commensal source and metabolite availability to sensing or uptake pathway, chromatin-modifying enzyme or epigenetic mark, target gene locus, responding immune cell type, and validated immune outcome remain to be limited. Future studies should integrate causal microbial genetics, longitudinal metabolomics, cell-type-resolved epigenomics, and human validation to distinguish causal mechanisms from associative findings and enable safe tissue- and patient-specific therapeutic translation. This review therefore outlines the microbiota-metabolite-epigenome axis as a unifying framework for local immunity while emphasizing the mechanistic gaps that must be addressed to develop effective therapeutic strategies.