Age-related gut dysbiosis contributes to age-related colitis and colon cancer risk and appears B7-H1-dependent. (HUM8P.352)

Abstract

Abstract Gut microbial imbalance (dysbiosis) can contribute to intestinal inflammation. Inflammation-driven colon cancer is a leading cause of death in the aged. We hypothesize that intestinal dysbiosis occurs with age and contributes to colon cancer susceptibility. We found that aged mice (~20 mos) had increased basal colon inflammation. Young mice (~3 mos) treated with AOM/DSS, an established model of inflammation-driven colon cancer, got transient colitis followed by colon cancer as expected. By striking contrast, aged mice on AOM/DSS developed severe, fatal, acute colitis preventing carcinogenesis studies. We also found that the colon microbiome is age-dependent. Gut flora-ablating antibiotics (abx) in young mice on AOM/DSS did not alter acute colitis or cancer. Strikingly, old mice on abx were highly protected from AOM/DSS-induced colitis and colon cancer, consistent with age-related dysbiosis causing increased risk for colitis and inflammation driven-colon cancer. PD-1 regulates gut flora in young mice and B7-H1 is its ligand. Aged B7-H1-/- mice given AOM/DSS, but no abx, did not develop acute colitis or colon cancer, suggesting that B7-H1 mediates age-related gut dysbiosis, inflammation and colon cancer risk. Taken together, our data suggest that age-related, B7-H1-dependent gut dysbiosis increases colon inflammation and susceptibility to colon carcinogenesis. Ongoing co-housing (WT/B7-H1 and young/aged) and other studies are defining specific immune mechanisms.