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

Abstract

Intake of Western diet stimulates bile acid (BA) production and their conversion to secondary BAs by 7α-dehydroxylating (7αDH+) bacteria in the colon. Increased levels of 7αDH+ bacteria and the secondary BA deoxycholic acid (DCA) have been associated with sporadic colorectal cancer (CRC). However, causal proof of their tumour-promoting effects under detrimental dietary conditions is lacking. Therefore, we performed feeding studies in a transgenic pig model of CRC combined with multi-omics analyses and gnotobiotic mouse studies. Western diet worsened the disease phenotype inAPC1311/+pigs. This was accompanied by increased levels of DCA and colonic epithelial cell proliferation, which was counteracted by using the bile acid-scavenging drug colestyramine. Using a gnotobiotic mouse model of CRC, we demonstrate that colonization with different 7αDH+ 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.