Abstract
It is well established that the intestinal microbiota plays a key role in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC) collectively referred to as inflammatory bowel disease (IBD). Epidemiological studies have provided strong evidence that IBD patients bear increased risk for the development of colorectal cancer (CRC). However, the impact of the microbiota on the development of colitis-associated cancer (CAC) remains largely unknown. In this study, we established a new model of CAC using azoxymethane (AOM)-exposed, conventionalized-Il10−/− mice and have explored the contribution of the host intestinal microbiota and MyD88 signaling to the development of CAC. We show that 8/13 (62%) of AOM-Il10−/− mice developed colon tumors compared to only 3/15 (20%) of AOM- wild-type (WT) mice. Conventionalized AOM-Il10−/− mice developed spontaneous colitis and colorectal carcinomas while AOM-WT mice were colitis-free and developed only rare adenomas. Importantly, tumor multiplicity directly correlated with the presence of colitis. Il10−/− mice mono-associated with the mildly colitogenic bacterium Bacteroides vulgatus displayed significantly reduced colitis and colorectal tumor multiplicity compared to Il10−/− mice. Germ-free AOM-treated Il10−/− mice showed normal colon histology and were devoid of tumors. Il10−/−; Myd88−/− mice treated with AOM displayed reduced expression of Il12p40 and Tnfα mRNA and showed no signs of tumor development. We present the first direct demonstration that manipulation of the intestinal microbiota alters the development of CAC. The TLR/MyD88 pathway is essential for microbiota-induced development of CAC. Unlike findings obtained using the AOM/DSS model, we demonstrate that the severity of chronic colitis directly correlates to colorectal tumor development and that bacterial-induced inflammation drives progression from adenoma to invasive carcinoma.
Highlights
The ability to mount an inflammatory response following injury or exposure to foreign organisms is vital for host homeostasis and survival
Bacterial-mediated colitis enhances colorectal tumorigenesis To investigate the role of bacterial-mediated colitis in the onset of colorectal carcinogenesis, conventionalized WT and Il102/2 mice were administered a regimen of AOM and monitored in vivo for signs of colitis and tumor development by colonoscopy at defined intervals (Fig. 1)
This is likely due to limitations posed by existing experimental models, which make it difficult to recapitulate the effects of chronic inflammation on colorectal tumorigenesis
Summary
The ability to mount an inflammatory response following injury or exposure to foreign organisms is vital for host homeostasis and survival. The etiology of IBD remains to be elucidated, animal model-based studies indicate that the host intestinal microbiota triggers an immune response that is requisite for the onset of disease [12,13,14,15]. This uncontrolled immune response likely represents a defect in one or more immunosuppressive mechanisms intended to provide tolerance to the host intestinal microbiota, resulting in the over-production of proinflammatory mediators [12,16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
