ena-STUDY-Georgia State University-07-01-2019-20:38:47:639-640
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.
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.