Weaning-Driven Gut Microbiome Shapes Intestinal Stem Cell Epigenetics to Train Immunological Memory (WGBS)

ABSTRACT: During weaning, the transition from milk to solid food rapidly expands and diversifies the gut microbiome, triggering the weaning reaction, a programmed immune response critical for long-lasting mucosal immunity. We characterized how these microbiome changes from weaning through young adulthood in mice shape the DNA methylome and transcriptome of intestinal stem cells (ISCs). We identified a weaning-induced IFN-g–TET3 axis as a key driver of MHC class II enhancer-linked epigenetic reprogramming, creating a transcriptional memory that persists through differentiation into adulthood. Early-life disruption of this axis, via IFN-g blockade or low-dose penicillin, impaired microbiota-mediated epigenetic control and mucosal immunity. Weaning-associated microbiome shifts enriched metabolites such as α-ketoglutarate, Fe2+, and methionine g-lyase, promoting TET-dependent DNA demethylation. These findings reveal how early-life events imprint lifelong epigenetic regulation of mucosal immunity, highlighting epithelial cells as innate immune sentinels that acquire trained transcriptional memory in response to microbial cues.

ORGANISM(S): Mus musculus

PROVIDER: GSE275219 | GEO | 2026/02/06

REPOSITORIES: GEO