Secondary bile acid production by gut bacteria promotes Western diet-associated colorectal cancer

Intake of Western diet stimulates bile acid (BA) production and their conversion to secondary BAs by 7alpha-dehydroxylating (7alphaDH+) bacteria in the colon. Increased levels of 7alphaDH+ bacteria and the secondary BA deoxycholic acid (DCA) have been associated with sporadic colorectal cancer (CRC), but causal proof of their tumour-promoting effects in a detrimental diet setting is lacking. Therefore, we performed feeding studies in a transgenic pig model of CRC combined with multi-omics analyses and gnotobiotic mouse studies. A Western diet worsened the polyp phenotype in APC1311/+ pigs. This was accompanied by increased levels of DCA and colonic epithelial cell proliferation, which was counteracted by using the drug colestyramine. Using a new gnotobiotic CRC mouse model, we demonstrate that colonization with different 7alphaDH+ bacterial isolates increased colonic tumour loads. These complementary approaches present clear evidence for the causal role of microbiome-derived DCA production in CRC, opening avenues for future preventive strategies.