Functional impact of bile acids conversion by the gut microbiome on colorectal cancer

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The human gut microbiota has been implicated in the development of colorectal cancer (CRC). The increased incidence of CRC in Westernized societies is linked to overall detrimental dietary habits accompanied by shifts in intestinal microbiota profiles. Epidemiological and microbiological studies point at the association between diet (e.g. increased fat and red meat consumption) and the incidence of CRC and at the underlying role of bile acids and their metabolism by gut bacteria. However, experimental evidence underpinning these relationships is lacking. In the present project, based on (i) own preliminary results demonstrating diet-induced shifts in the gut microbiome linked to worsening of pathology in the unique APC1311/+ pig model of CRC, and (ii) our state-of-the-art collection of bacterial strains isolated from the pig intestine, we will provide novel mechanistic insights into the causal role of secondary bile acids in CRC using fecal microbiota transfer experiments and defined bacterial communities. We will use the newly generated germfree Apc1638/N mouse model of disease in combination with molecular methods, including microbiota and single-cell RNA sequencing as well as metabolic profiling to assess changes affecting both the microbial ecosystem and host pathophysiology. For mechanistic understanding of the microbial ecology of bile acid metabolism and towards interventional strategies, we will utilize phages targeting secondary bile acid-producing bacteria and test their impact on community dynamics using minimal bacterial consortia in continuous culture systems. Taken together, this project will deliver important insights into the functional role of gut microbiome activities in CRC using innovative pre-clinical models.