Epigenetic phase variation in the gut microbiome enhances bacterial adaptation

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Abstract
"The human gut microbiome continuously adapts to fluctuations in diet, medication, and host physiology, yet the mechanisms enabling rapid bacterial adaptation remain incompletely understood. Epigenetic phase variation (ePV), mediated by DNA methylation, can generate phenotypic heterogeneity within clonal bacterial populations, but its prevalence and functional roles in commensal gut bacteria are largely unexplored. Here, we systematically characterize ePVs across the human gut microbiome using long-read metagenomics coupled with integrative transcriptomic analysis. We identify both genome-wide and site-specific ePVs, including genome-wide methylation switching driven by structural variation of DNA methyltransferases. Analysis of large-scale public metagenomic datasets reveals that such genome-wide ePVs are widespread across both healthy and disease-associated microbiomes. We further show that ePVs dynamically respond to environmental perturbations, including antibiotic exposure, fecal microbiota transplantation, and probiotic engraftment. Focusing on an Akkermansia muciniphila isolate, we identify a specific ePV regulating mucC, whose expression enhances bacterial tolerance to antibiotics, consistent with a bet-hedging adaptive strategy. Together, our findings uncover epigenetic heterogeneity as a pervasive and functionally important mechanism of bacterial adaptation in the human gut, providing a new framework for understanding microbiome dynamics in health and disease."

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