Weaning drives microbiome-mediated epigenetic regulation to shape immune memory in mice

Authors: YANG, LI - Children'S Nutrition Research Center (CNRC); PEERY, ROBERT - Children'S Nutrition Research Center (CNRC); ZHOU, SHIRUI - Tongji University; CHEN, XIAOMIN - Children'S Nutrition Research Center (CNRC); FARMER, LEAH - Children'S Nutrition Research Center (CNRC); GUTIERREZ, FABIOLA - Baylor College Of Medicine; FOWLER, STEPHANIE - Baylor College Of Medicine; ZHANG, LANJING - Rutgers University; SALAMAT, JULIA - Children'S Nutrition Research Center (CNRC); RIGGINS, KAREN - Baylor College Of Medicine; SHI, JIEJUN - Tongji University; SHEN, LANLAN - Children'S Nutrition Research Center (CNRC)

Submitted to: Nature Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/12/2026
Publication Date: 3/19/2026
Citation: Yang, L., Peery, R.C., Zhou, S., Chen, X., Farmer, L.M., Gutierrez, F., Fowler, S., Zhang, L., Salamat, J.M., Riggins, K., Shi, J., Shen, L. 2026. Weaning drives microbiome-mediated epigenetic regulation to shape immune memory in mice. Nature Microbiology. 11:1064-1079. https://doi.org/10.1038/s41564-026-02295-6.
DOI: https://doi.org/10.1038/s41564-026-02295-6

Interpretive Summary: The weaning transition, when diet shifts from milk to solid food, is a critical window that permanently shapes gut immune development. This study shows that the gut microbiome, responding to early dietary changes, modifies DNA methylation in intestinal stem cells through an interferon-gamma–dependent pathway, creating lasting immune "memory" at genes controlling pathogen recognition. When early microbial signals were disrupted by antibiotic treatment or blocked immune signaling, this epigenetic programming failed and animals developed more severe intestinal inflammation upon later challenge. These findings have direct relevance to USDA priorities: early-life feeding practices and microbiome management are not simply matters of growth performance, but are determinants of long-term immune resilience and disease resistance. Nutritional strategies that support a healthy weaning-period microbiome may offer a practical, low-intervention approach to improving gut health outcomes in agricultural and public health settings.

Technical Abstract: During weaning, the transition to solid food diversifies the gut microbiome, triggering a programmed immune response critical for long-lasting mucosal immunity. Previous work showed that the gut microbiome mediates epigenetic development in intestinal stem cells (ISCs) during suckling, but what happens during weaning is unclear. Here, genome-wide profiling revealed that weaning-driven microbiome changes shape the DNA methylome and transcriptome of murine ISCs in an IFN'-dependent manner. Specifically, we observe demethylation of enhancer elements essential for MHC class II genes, which results in a transcriptional memory that persists through differentiation into adulthood. IFN' blockade, or low-dose penicillin to target Gram-positive bacteria, in early life impaired microbiome-mediated epigenetic control and mucosal immunity, and exacerbated colitis. Murine organoids primed with IFN' showed rapid, amplified transcriptional responses upon secondary stimulations. These findings reveal that early-life events alter the gut microbiome and these changes reprogramme ISC epigenetic memory to shape mucosal immunity.