Impact of gut microbiota and segmented filamentous bacteria on colitis-associated colorectal cancer

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 DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second most common cause of cancer-related mortality in developed countries. Chronic gastrointestinal (GI) inflammation, as occurs in inflammatory bowel disease (IBD), is one of the primary risk factors for the development of colorectal cancer. Recent evidence suggests that the complex community of bacteria present in the GI tract (gut microbiota; GM) has a tremendous impact on host health, particularly in diseases such as IBD and CRC. Additionally, there is evidence that the GM of healthy individuals can be clustered into a limited number of distinct compositions called enterotypes. The impact of these various enterotypes on disease risk is unknown. One particular bacterial species (segmented filamentous bacteria; SFB) has recently gained considerable attention due to its myriad effects on the mucosal immune system and an apparent correlation with ulcerative colitis, one form of IBD. Notably however, the methodologies needed to adequately characterize the largely uncultivable bacteria present in the GM have not existed long enough to track humans longitudinally from the time prior to disease development to the point at which CRC is diagnosed. Thus, existing data on the role of the GM in CRC are correlative and do not demonstrate a causal relationship. Additionally, the GM is acquired beginning at birth and does not normalize to its stable adult composition until some point in childhood or early adolescence. It is unknown whether the risk of CRC later in life is determined during the initial colonization of the gut, or if disease risk can be modulated later in life throuh changes in the GM. The proposed studies will answer these questions through the use of a mouse model with distinct similarities to the human condition. In this model, CRC is induced in mice carrying a genetic mutation affecting a pathway implicated in the development of human CRC. Disease is initiated via experimental inoculation with a weakly opportunistic pathogen shown to induce host immune responses to other non-pathogenic, commensal bacteria, thus mimicking the environment present in individuals at high risk of CRC such as those diagnosed with IBD. This model will allow disease to be tracked longitudinally through all stages of disease development, and will allow for the controlled, prospective assessment of experimental treatments. While the specific microbes present in the GM of humans and mice differ, there are highly conserved functional properties of higher microbial taxa, e.g., family or class. Thus, data generated in the proposed studies will be translatable to humans and will direct the design of subsequent experiments. Moreover, metabolomic profiling will serve to identify differences between individuals that do or do not progress to CRC, in the function of the GM. Of note, these findings will inform the development of both diagnostic and therapeutic modalities for use in humans and could have far-reaching consequences in the fields of oncology and gastroenterology.