DESCRIPTION (provided by applicant): Emerging evidence links gut microbiota to the development and progression of colon cancer (CoCA). Interestingly, obesity is a significant driver for the composition of gut microbiota. However, there are no studies that have directly examined the influence of gut microbiota on driving obesity-enhanced CoCA. The tumor- promoting effects of the microbiota in CoCA are caused, at least in part, by altered host-microbial interactions. Host-derived immune and inflammatory responses are important driving forces that shape microbial community composition and, when altered, may contribute to dysbiosis. Macrophages (MΦs) are a primary source of obesity-associated inflammation and have been linked to poor prognosis in CoCA. However, there are no studies that have systematically examined a role for MΦs in altering the gut microbial profile in obesity- enhanced CoCA. The long-term goal is to uncover the mechanisms linking obesity to CoCA. The objective in this particular investigation is to determine the influence of an obesity-induced alteration in ut microbiota on CoCA progression and to test whether this process is regulated by MΦs. The central hypothesis is that obesity-induced changes in gut microbiota are driven by MΦ-mediated inflammatory processes and lead to enhanced progression of CoCA. This hypothesis will be tested by pursuing two specific aims: 1) Determine the effects of an obesity-induced alteration in gut microbiota on CoCA; and 2) Evaluate the role of MΦs in altering the gut microbial profile in obesity-enhanced CoCA. Under the first aim, we will test the hypothesis that obesity can enhance CoCA by altering gut microbiota. Using an inducible genetic mouse model of colon cancer, we will examine the effects of diet-induced obesity on the gut microbial profile and subsequent progression of tumorigenesis. Further, we will transfer gut microbes from obese mice to lean mice carrying an inducible Apc mutation to test the influence of an obesity-induced alteration of gut microbiota on CoCA progression. Finally, using antibiotics we will deplete gut microflora from obese mice to further confirm the role of obesity-induced alterations in gut microbiota on CoCA. In the second aim, we will test the hypothesis that MΦs play a necessary role in altering gut microbiota in obesity-enhanced CoCA. Using MΦ depletion techniques, we will examine the role of MΦs in altering the gut microbial profile and subsequently promoting progression of tumorigenesis in a mouse model of obesity-enhanced CoCA. Further, using adoptive transfer of MΦs from obese mice to lean mice carrying an inducible Apc mutation, we will directly determine their effects on gut microbiota and CoCA progression. The proposed investigation is significant as it will uncover a mechanism that links obesity to CoCA. Understanding the impact of obesity-induced alterations in gut bacteria on CoCA will allow us to translate to the development of approaches that will identify individuals at risk for CoCA. This would present enormous potential for prevention of CoCA in obese individuals through development of personalized dietary intervention strategies designed to restore a more healthy microbial profile in the gut.

PUBLIC HEALTH RELEVANCE: Obesity-induced alterations in gut bacteria may increase the risk for colon tumorigenesis. Inflammatory processes are likely to play a role in this response given their ability to shape the composition of gut bacteria. The overall goal of this proposed study is to determine the influence of an obesity-induced alteration in gut microbiota on colon cancer progression and to test whether this process is regulated by pro-inflammatory macrophages.