Imprinting of regulatory T cells by gut microbiota early in life 2336688

Abstract

The gut microbiota is essential for immune system maturation in early life. The introduction of solid food at weaning triggers a transient immune response, the weaning reaction, which protects against colitis and colorectal cancer later in life. However, the impact of dietary-induced microbial dysbiosis during weaning on long-term intestinal homeostasis remains unclear. We aimed to determine whether and how microbial dysbiosis during weaning affects mucosal homeostasis and susceptibility to colitis and colorectal cancer in adulthood. Mice were fed diets differing in fiber quantities during weaning. After weaning, offspring were maintained on standard chow. Microbiota composition, and intestinal immune cell populations were studied. Adult susceptibility was evaluated using DSS-induced colitis, AOM/DSS-induced colitis-associated cancer, and spontaneous intestinal cancer (ApcMin/+) models. To study the contribution of T cells, scRNA-seq was performed on CD4-positive T cells, and transgenic mice were used to track specific, transient CD4+ T cell subsets. Bulk RNA-seq of the colon and T cell transfer experiments were also conducted. The causal role of early-life microbiota was tested by transferring microbiota into germ-free mice. Early-life dietary variation induced subtle changes in microbiota, reflected in shifts in immune cell populations at weaning. These early differences were associated with altered adult responses to colitis and colorectal cancer, indicating lasting effects on mucosal homeostasis. Specific CD4+ T cell subsets were modulated by early-life microbiota, and colon transcriptomics revealed persistent changes. Microbiota transfer into germ-free neonates demonstrated that early-life microbial communities alone were sufficient to shape long-term intestinal outcomes, highlighting a critical window during weaning for immune programming. Microbial composition during weaning plays a central role in establishing long-term mucosal homeostasis. This project supported by the European Research Council Starting Grant, Swiss National Science Foundation, Helmut Horten Stiftung, Swiss Cancer Research Foundation, Kenneth Rainin Foundation, Inselspital, Ruth & Arthur Scherbarth Stiftung, Novartis Founda Mucosal and Regional Immunology (MUC)