Early life microbiota exposure restricts myeloid-derived suppressor cell driven colonic tumorigenesis

Gut microbiota and their metabolites are instrumental in regulating homeostasis at intestinal and extra-intestinal sites. However, the complex effects of prenatal and early postnatal microbial exposure on adult health and disease outcomes remain incompletely understood. Here we show that mice raised under germ-free conditions until weaning and then transferred to specific-pathogen free conditions, harbor altered microbiota composition, augmented inflammatory cytokine and chemokine expression, and are hyper-susceptible to colitis-associated tumorigenesis later in adulthood. Dramatically increased numbers and size of colon tumors and intestinal epithelial proliferation in recolonized germ-free mice were associated with augmented intratumoral CXCL1, CXCL2, CXCL5 expression and granulocytic myeloid-derived suppressor cell accumulation. Consistent with these findings, CXCR2 neutralization in recolonized germ-free mice completely reversed the exacerbated susceptibility to colitis-associated tumorigenesis. Collectively, our findings highlight a crucial role for early life microbial exposure in establishing intestinal homeostasis that restrains colon cancer in adulthood.