Influence of Bile Acids on Colorectal Cancer Risk: Potential Mechanisms Mediated by Diet - Gut Microbiota Interactions

Abstract

Purpose of review: To review the evidence for the tumorigenic effects of food-stimulated bile acids on the colon and interaction with the gut microbiota.

Recent findings: High-fat diets promote the hepatic synthesis of bile acids and increase their delivery to the colonic lumen. Here, they stimulate the growth and activity of 7α-dehydroxylating bacteria, which convert primary into secondary bile acids that show tumorigenic activity, especially deoxycholic acid (DCA). Fecal levels of secondary bile acids correlate with mucosal and metabolic markers of colorectal cancer (CRC) risk in high and low risk adult individuals and can be modified within a few weeks by dietary change. While gut bacteria regulate the bile acid pool via complex microbial biotransformation, bile acids alter the gut microbiota composition due to their antimicrobial properties. This mutual reaction induces altered bile acid pools and dysbiotic compositions of the gut microbiota that may show tumor-promoting activity of bile acids beyond their conversion to DCA.

Summary: Bile acids act as tumor promoters in the colon. Diet and the gut microbiota are most likely the key drivers that mediate and confer bile acid-associated tumorigenic activity. Bacterial conversion of bile acids in the colon has a significant impact on their tumorigenic activity, substantiating the hypothesis that diet affects CRC risk through its effects on colonic microbial metabolism.

Keywords: Colorectal cancer; bile acids; deoxycholic acid; gut microbiota; high-fat diet.

Figure 1. Impact of high-fat diet and selected biotransformations by the gut microbiota on tumor-promoting activity of bile acids in the intestine

The repeated intake of a high-fat diet stimulates the hepatic synthesis of bile acids (BA), their conjugation with taurine and the secretion into the duodenum providing high levels of primary BA in the gut lumen. The deconjugation of BA by microbial bile salt hydrolases results in increased luminal levels of taurine, which promotes the growth of single members of the gut microbiota, and high levels of unconjugated BA that enter the colon, where they are converted to secondary BA by 7α-dehydroxylating bacteria. This promotes high colonic concentrations of secondary BA, especially deoxycholic acid (DCA), which has tumorigenic activity and drives a dysbiotic composition of the colonic microbiota featuring increased abundance of 7α-dehydroxylating bacteria and microbes with potential genotoxic activity. The enhanced 7α-dehydroxylation capacity of the gut microbiota leads to an altered BA pool with higher levels of DCA entering enterohepatic circulation. Cholic acid (CA), chenodeoxycholic acid (CDCA), lithocholic acid (LCA).