Interactions between bile salts, gut microbiota, and hepatic innate immunity

Abstract

Bile salts are the water-soluble end products of hepatic cholesterol catabolism that are released into the duodenum and solubilize lipids due to their amphipathic structure. Bile salts also act as endogenous ligands for dedicated nuclear receptors that exert a plethora of biological processes, mostly related to metabolism. Bile salts are actively reclaimed in the distal part of the small intestine, released into the portal system, and subsequently extracted by the liver. This enterohepatic cycle is critically dependent on dedicated bile salt transporters. In the intestinal lumen, bile salts exert direct antimicrobial activity based on their detergent property and shape the gut microbiota. Bile salt metabolism by gut microbiota serves as a mechanism to counteract this toxicity and generates bile salt species that are distinct from those of the host. Innate immune cells of the liver play an important role in the early recognition and effector response to invading microbes. Bile salts signal primarily via the membrane receptor TGR5 and the intracellular farnesoid-x receptor, both present in innate immune cells. In this review, the interactions between bile salts, gut microbiota, and hepatic innate immunity are discussed.

Potential mechanisms linking gut microbiota and portal hypertension

“…Due to their greater hydrophobicity, secondary bile acids are more toxic to bacteria. Thus, bacterial strains that possess BSH activity may substantially alter the bile acid pool and its bactericidal properties . Bile acid metabolism in the host is rate‐limited by cholesterol‐7α‐hydroxylase (CYP7A1) under the negative control of farnesoyl‐X‐receptor (FXR), a nuclear receptor preferentially activated by primary bile acids and expressed in the intestinal epithelium and the liver .…”

“…Thus, bacterial strains that possess BSH activity may substantially alter the bile acid pool and its bactericidal properties . Bile acid metabolism in the host is rate‐limited by cholesterol‐7α‐hydroxylase (CYP7A1) under the negative control of farnesoyl‐X‐receptor (FXR), a nuclear receptor preferentially activated by primary bile acids and expressed in the intestinal epithelium and the liver . Another major bile acid sensor is the G‐protein–coupled receptor TGR5, preferentially activated by secondary bile acids and expressed on the surface of many cells .…”

“…Another major bile acid sensor is the G‐protein–coupled receptor TGR5, preferentially activated by secondary bile acids and expressed on the surface of many cells . Biological functions of FXR extend into regulation of lipid, carbohydrate and amino acid metabolism, protection of gut barrier integrity, and production of antimicrobial peptides, while TGR5 reduces pro‐inflammatory responses in macrophages, inhibits activation of the NLRP3 inflammasome and regulates eNOS activity in SECs . Since the promoter of human eNOS contains cAMP‐responsive elements and cAMP is one of the known mediators of TGR5, a “bile acid–TGR5–cAMP pathway” has been implicated in the control eNOS‐mediated NO release, further cementing the relationship between the gut microbiota and sinusoidal homeostasis …”

“…Thus, due to a reduced pool of secondary bile acids reaching the colon, strong antimicrobial activity may be absent in cirrhosis and likely contributes to the increased prevalence of SIBO and weakening of the gut barrier . Moreover, increasingly altered bile acid metabolism in cirrhosis may further compromise bile acid‐mediated FXR and TGR5 signalling and their biological impact on sinusoidal vasoregulation …”

“…Thus, bacterial strains that possess BSH activity may substantially alter the bile acid pool and its bactericidal properties. 15,36 Bile acid metabolism in the host is rate-limited by cholesterol-7α-hydroxylase (CYP7A1)…”