How microbes reprogram immunity through epigenetic and epitranscriptomic regulation

Abstract Microbial communities shape immunity through antigens, structural ligands, and metabolites, but how these transient signals are translated into stable, reversible, or disease-promoting immune cell states remains incompletely understood. This review examines epigenetic and epitranscriptomic regulation as interconnected layers of host-microbiota interactions. We discuss how microbial signals engage chromatin- and RNA-regulatory pathways across epithelial, myeloid, lymphoid, and stromal compartments, placing the microbiota- N 6 -methyladenosine (m 6 A) axis within the broader landscape of host and microbial RNA modifications. This framework helps explain how the same microbial molecule can promote barrier repair, immune tolerance, inflammation, or antitumor immunity depending on tissue exposure, responding cell type, and host state. We distinguish between association, microbiota dependence, and direct regulatory causality, and highlight knowledge gaps concerning non-m 6 A RNA modifications and bidirectional regulatory mechanisms. Finally, we outline key experimental and translational considerations, including microbial function, host target engagement, cell specificity, spatial delivery, and disease context. These insights highlight chromatin and RNA regulation as potential mechanistic links between microbial ecology and immune function that welcome further experimental investigation.