Guts and Gall: Bile Acids in Regulation of Intestinal Epithelial Function in Health and Disease

Abstract

Epithelial cells line the entire surface of the gastrointestinal tract and its accessory organs where they primarily function in transporting digestive enzymes, nutrients, electrolytes, and fluid to and from the luminal contents. At the same time, epithelial cells are responsible for forming a physical and biochemical barrier that prevents the entry into the body of harmful agents, such as bacteria and their toxins. Dysregulation of epithelial transport and barrier function is associated with the pathogenesis of a number of conditions throughout the intestine, such as inflammatory bowel disease, chronic diarrhea, pancreatitis, reflux esophagitis, and cancer. Driven by discovery of specific receptors on intestinal epithelial cells, new insights into mechanisms that control their synthesis and enterohepatic circulation, and a growing appreciation of their roles as bioactive bacterial metabolites, bile acids are currently receiving a great deal of interest as critical regulators of epithelial function in health and disease. This review aims to summarize recent advances in this field and to highlight how bile acids are now emerging as exciting new targets for disease intervention.

Western diet‐induced increase in colonic bile acids compromises epithelial barrier in nonalcoholic steatohepatitis

“…[19][20][21][22] The extent of BAinduced cytotoxicity and subsequent tissue injury depends on the conjugation status, concentration, and the duration of exposure. 36 At abnormally high concentrations, BAs disrupt cell membranes, cause oxidative/nitrosative stress, and apoptosis. 23,36,37 In contrast, prolonged exposure to high concentrations of BAs results in genomic instability and apoptosis resistance, which can lead to the development of cancer.…”

“…36 At abnormally high concentrations, BAs disrupt cell membranes, cause oxidative/nitrosative stress, and apoptosis. 23,36,37 In contrast, prolonged exposure to high concentrations of BAs results in genomic instability and apoptosis resistance, which can lead to the development of cancer. 38,39 Our results demonstrate an association between elevated cecal BA levels, including the highly cytotoxic primary BA, CDCA, and colonic epithelial injury in WD-fed mice.…”

Bile acid supplementation improves murine pancreatitis in association with the gut microbiota

“…Our group has previously reported dramatically changed intestinal microbiota in rats with pancreatitis, and we were able to improve the intestinal microbiota imbalance of theses rats with anti-inflammatory therapy [9]. Evidence also indicates that bile acids are involved in the development of AP, but the exact mechanisms underlying this association are unclear, especially in non-biliary pancreatitis [10].…”

Microbial Metabolites and Intestinal Stem Cells Tune Intestinal Homeostasis

“…Primary bile acids, for example, cholic acid (CA) and chenodeoxycholic acid (CDCA) in human, and CA, CDCA, and muricholic acid (MCA) in rodents, are synthesized, conjugated with taurine or glycine in liver, and discharged into biliary tract and proximal small intestine for lipid solubilization and metabolism. [ 21,135 ] Most bile acids are re‐absorbed in the terminal ileum, whereas a small portion is carried to the colon and transformed by colonic microbes to secondary bile acids, mainly deoxycholic acid (DCA) and lithocholic acid (LCA). [ 21,135,136 ] Secondary bile acids have long been suspected to contribute to colorectal cancer development due to a strong link between diet‐induced high levels of secondary bile acids and intestinal cancer occurrence, [ 137,138 ] suggestive of a role for secondary bile acids on intestinal stem cell proliferation.…”

“…[ 20 ] Imbalance in intestinal epithelial cell regeneration may result in various intestinal abnormalities, such as compromised gut barrier or cancer development. [ 21 ] It is thus crucial to understand the interactions between diverse microbial metabolites and intestinal stem cells, and its influence on intestinal homeostasis. [ 22 ]…”