Modulation of intestinal bile acids influences colonic mucosal responses.

BACKGROUND

Elevated levels of secondary bile acids produced by the gut microbiome, in particular deoxycholic acid (DCA), influence epithelial cell proliferation and accelerate the development of colorectal cancer (CRC) under adverse dietary conditions, such as long-term, high fat intake. However, their effects on the intestinal epithelium have not been studied in detail.

AIM: To determine gut epithelial responses to bile acid modulation in vivo and in situ.

METHODS

We performed targeted colonization of gnotobiotic mice followed by single-cell RNA sequencing (scRNA-Seq) of colonic epithelial cells combined with immunostaining of human biopsies from: (i) an observational patient cohort with hyperproliferative polyps or cancer; (ii) an interventional study with bile acid-scavenging drugs.

RESULTS

Colonization of mice with a defined bacterial community including the 7α-dehydroxylating species Extibacter muris resulted in DCA production. ScRNA-Seq of colonic epithelial cells revealed increased cell density of bile acid-sensitive enterocytes but fewer stem cells, goblet cells, and transit amplifying cells in mice exposed to DCA. This was associated with increased expression of pyruvate dehydrogenase kinase (Pdk4) and decreased expression of mucin (Muc2). PDK expression was also increased in human hyperplastic polyps and adenomas, whilst MUC2 expression was reduced in adenomas and carcinomas compared to normal mucosa. In addition, treatment of ileostomy patients with chologenic diarrhea using bile acid sequestrants was associated with enhanced epithelial proliferation in colorectal biopsies.

CONCLUSION

This study provides insight into intestinal epithelial cell responses to bile acids and their potential clinical relevance.