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

ABSTRACT: During weaning, the shift from milk to solid food is accompanied by a rapid expansion and diversification of the gut microbiome. This triggers the weaning reaction, a programmed immune response important for long-lasting mucosal immunity that is poorly understood. Here, we characterize the impact of the gut microbiome on the DNA methylome and transcriptome of intestinal stem cells (ISCs) from weaning to young adulthood in mice. We identify a weaning- IFN-g-TET3 axis that reprograms epithelial MHC-II signaling via enhancer demethylation in ISCs, establishing a lasting transcriptional memory into adulthood. Disruption of this axis by IFN-g blockade or low-dose penicillin attenuates the microbiota-mediated epigenetic control of epithelial MHC-II signaling, leading to impaired mucosal immunity. By engaging immune crosstalk and metabolite production, the weaning microbiome drives epigenetic reprogramming, thereby establishing a microbiome-induced regulatory pathway that couples developmental cues to lifelong epithelial immune resilience.

ORGANISM(S): Mus musculus

PROVIDER: GSE310995 | GEO | 2026/02/06

REPOSITORIES: GEO

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Project description:On going efforts are directed at understanding the mutualism between the gut microbiota and the host in breast-fed versus formula-fed infants. Due to the lack of tissue biopsies, no investigators have performed a global transcriptional (gene expression) analysis of the developing human intestine in healthy infants. As a result, the crosstalk between the microbiome and the host transcriptome in the developing mucosal-commensal environment has not been determined. In this study, we examined the host intestinal mRNA gene expression and microbial DNA profiles in full term 3 month-old infants exclusively formula fed (FF) (n=6) or breast fed (BF) (n=6) from birth to 3 months. Host mRNA microarray measurements were performed using isolated intact sloughed epithelial cells in stool samples collected at 3 months. Microbial composition from the same stool samples was assessed by metagenomic pyrosequencing. Both the host mRNA expression and bacterial microbiome phylogenetic profiles provided strong feature sets that clearly classified the two groups of babies (FF and BF). To determine the relationship between host epithelial cell gene expression and the bacterial colony profiles, the host transcriptome and functionally profiled microbiome data were analyzed in a multivariate manner. From a functional perspective, analysis of the gut microbiota's metagenome revealed that characteristics associated with virulence differed between the FF and BF babies. Using canonical correlation analysis, evidence of multivariate structure relating eleven host immunity / mucosal defense-related genes and microbiome virulence characteristics was observed. These results, for the first time, provide insight into the integrated responses of the host and microbiome to dietary substrates in the early neonatal period. Our data suggest that systems biology and computational modeling approaches that integrate “-omic” information from the host and the microbiome can identify important mechanistic pathways of intestinal development affecting the gut microbiome in the first few months of life. KEYWORDS: infant, breast-feeding, infant formula, exfoliated cells, transcriptome, metagenome, multivariate analysis, canonical correlation analysis 12 samples, 2 groups

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

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