The Protective Role of <i>Bacteroides fragilis</i> in a Murine Model of Colitis-Associated Colorectal Cancer

Abstract

Many patients with chronic inflammation of the gut, such as that observed in inflammatory bowel disease (IBD), develop colorectal cancer (CRC). Recent studies have reported that the development of IBD and CRC partly results from an imbalanced composition of intestinal microbiota and that intestinal inflammation in these diseases can be modulated by the microbiota. The human commensal <i>Bacteroides fragilis</i> is best exemplified playing a protective role against the development of experimental colitis in several animal disease models. In this study, we found that gut inflammation caused by dextran sulfate sodium (DSS) treatment was inhibited by <i>B. fragilis</i> colonization in mice. Further, we reveal a protective role of <i>B. fragilis</i> treatment against colon tumorigenesis using an azoxymethane (AOM)/DSS-induced model of colitis-associated colon cancer in mice and demonstrate that the decreased tumorigenesis by <i>B. fragilis</i> administration is accompanied by inhibited expression of C-C chemokine receptor 5 (CCR5) in the gut. We show direct evidence that the inhibition of tumor formation provided by <i>B. fragilis</i> in colitis-associated CRC animals was dependent on the production of polysaccharide A (PSA) from <i>B. fragilis</i> and that Toll-like receptor 2 (TLR2) signaling was responsible for the protective function of <i>B. fragilis</i><b>IMPORTANCE</b> The incidence of colorectal cancer (CRC) is rapidly growing worldwide, and there is therefore a greater emphasis on studies of the treatment or prevention of CRC pathogenesis. Recent studies suggested that consideration of the microbiota is unavoidable to understand inflammation and tumorigenesis in the gastrointestinal tract. We demonstrate, using a mouse model of colitis-associated CRC, that human commensal <i>B. fragilis</i> protects against colon tumorigenesis. The protective role against tumor formation provided by <i>B. fragilis</i> is associated with inhibition of expression of the chemokine receptor CCR5 in the colon. The molecular mechanism for protection against CRC provided by <i>B. fragilis</i> is dependent on polysaccharide A production and is mediated by TLR2 signaling. Our results suggest that the commensal microorganism <i>B. fragilis</i> can be used to prevent inflammation-associated CRC development and may provide an effective therapeutic strategy for CRC.