Interaction of gut microbiota with dysregulation of bile acids in the pathogenesis of nonalcoholic fatty liver disease and potential therapeutic implications of probiotics

J Cell Biochem. 2019 Mar;120(3):2713-2720. doi: 10.1002/jcb.27635. Epub 2018 Nov 15.

Abstract

The intestinal microbiota is now recognised to play key roles in health due to its involvement in many aspects of human physiology. Disturbance in gut microbiota (dysbiosis) is thus associated with many diseases including nonalcoholic fatty liver disease (NAFLD) which includes nonalcoholic fatty liver and nonalcoholic steatohepatitis. The mechanisms for the effect of dysbiosis in NAFLD pathogenesis are not completely elucidated. Many explanations have been proposed to trigger dysbiosis, leading to NAFLD including inflammation, ethanol produced by the gut bacteria and lipotoxicity. Recently the roles of bile acids and nuclear receptors are highly regarded. It is well known that gut microbes produce enzymes that convert primary bile acids into secondary bile acids in the intestines. Several studies have demonstrated that disturbance of the intestinal microbiota leads to decreased synthesis of secondary bile acids, which in turn decreases activation of nuclear receptors such as farnesoid X receptor (FXR), pregnane X receptor, Takeda G-protein-coupled bile acid protein 5 and vitamin D receptor. These receptors are important in energy regulation and their dysregulation can cause NAFLD. Therefore, stimulation of nuclear receptors especially FXR has been extensively explored for the amelioration of NAFLD. However, paradoxical effects of nuclear receptor activation are a major problem for the clinical application of nuclear receptor stimuli. We further posit that microbiome restoration could be an alternative approach for the treatment of NAFLD. Several gut bacteria are now known to be involved in bile acid metabolism. It will be necessary to identify which one/ones is/are feasible. Careful selection of commensal bacteria for probiotics may lead to an effective therapy for NAFLD.

Keywords: CA; CDCA; DCA; LCA; Takeda G-protein-coupled bile acid protein 5; farnesoid X receptor; gut microbiota; nonalcoholic steatohepatitis.

Publication types

  • Review

MeSH terms

  • Animals
  • Bile Acids and Salts / metabolism*
  • Gastrointestinal Microbiome* / drug effects
  • Humans
  • Non-alcoholic Fatty Liver Disease / microbiology*
  • Non-alcoholic Fatty Liver Disease / therapy*
  • Probiotics / pharmacology
  • Probiotics / therapeutic use*
  • Receptors, Cytoplasmic and Nuclear / metabolism

Substances

  • Bile Acids and Salts
  • Receptors, Cytoplasmic and Nuclear