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

BACKGROUND

Western diet and associated production of secondary bile acids (BAs) have been linked to the development of sporadic colorectal cancer (CRC). Despite observational studies showing that secondary BAs produced by 7α-dehydroxylating (7αDH+) gut bacteria are increased in CRC, a causal proof of their tumour-promoting effects is lacking.

OBJECTIVE

Investigate the causal role of BAs produced by 7αDH+ gut bacteria in CRC.

DESIGN

We performed feeding studies in a porcine model of CRC combined with multi-omics analyses and gnotobiotic mouse models colonised with 7αDH+ bacteria or a genetically modified strain to demonstrate causality.

RESULTS

Western diet exacerbated the CRC phenotype in APC 1311/+ pigs. This was accompanied by increased levels of the secondary BA deoxycholic acid (DCA) and higher colonic epithelial cell proliferation. The latter was counteracted by the BA-scavenging drug colestyramine. Metagenomic analysis across multiple human cohorts revealed higher occurrence of bai (BA inducible) operons from Clostridium scindens and close relatives in faeces of patients with CRC. Addition of these specific 7αDH+ bacteria (C. scindens/Extibacter muris) to defined communities of gut bacteria led to DCA production and increased colon tumour burden in mouse models of chemically or genetically induced CRC. A mutant strain of Faecalicatena contorta lacking 7αDH caused fewer colonic tumours in azoxymethane/dextran sodium sulfate treated mice and triggered less epithelial cell proliferation in human colon organoids compared with wild-type F. contorta.

CONCLUSION

This work provides functional evidence for the causal role of secondary BAs produced by gut bacteria through 7αDH in CRC under adverse dietary conditions, opening avenues for future preventive strategies.