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

Abstract

AbstractWestern diet is an important risk factor for the development of sporadic colorectal cancer (CRC). Dietary fat stimulates bile acid (BA) production by the host and their conversion to secondary BAs by 7α-dehydroxylating (7αDH+) bacteria, but causal proof of their tumor-promoting effectsin vivois lacking. To address this, we performed feeding studies in a genetically engineered 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 microbiota changes, increased levels of the secondary bile acid deoxycholic acid (DCA), and higher colonic epithelial cell proliferation. The latter was counteracted by using the BA-scavenging drug colestyramine. Metagenomic analysis across multiple cohorts revealed higher occurrence ofbai(BA inducible) operons fromClostridium scindensand close relatives in stool of CRC subjects (n = 1,034). Using two gnotobiotic mouse models of CRC, we demonstrate that colonization with 7αDH+ bacteria (C. scindensorExtibacter muris) increased colonic tumor loads. This work provides clear evidence for the causal role of microbiome-derived DCA production in CRC under detrimental dietary conditions, opening avenues for future preventive strategies.