Modulation of the Intestinal Microbiota Alters Colitis-Associated Colorectal Cancer Susceptibility

摘要: It is well established that the intestinal microbiota plays a key role in pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC) collectively referred to as inflammatory bowel (IBD). Epidemiological studies have provided strong evidence IBD patients bear increased risk for development colorectal cancer (CRC). However, impact on colitis-associated (CAC) remains largely unknown. In this study, we new model CAC using azoxymethane (AOM)-exposed, conventionalized-Il10−/− mice explored contribution host MyD88 signaling CAC. We show 8/13 (62%) AOM-Il10−/− developed colon tumors compared only 3/15 (20%) AOM- wild-type (WT) mice. Conventionalized spontaneous carcinomas while AOM-WT were colitis-free rare adenomas. Importantly, tumor multiplicity directly correlated with presence colitis. Il10−/− mono-associated mildly colitogenic bacterium Bacteroides vulgatus displayed significantly reduced Germ-free AOM-treated showed normal histology devoid tumors. Il10−/−; Myd88−/− treated AOM expression Il12p40 Tnfα mRNA no signs development. present first direct demonstration manipulation alters The TLR/MyD88 pathway essential microbiota-induced Unlike findings obtained AOM/DSS model, demonstrate severity chronic correlates bacterial-induced inflammation drives progression from adenoma invasive carcinoma.