Bile acids and the gut microbiota: metabolic interactions and impacts on disease

Abstract

Despite decades of bile acid research, diverse biological roles for bile acids have been discovered recently due to developments in understanding the human microbiota. As additional bacterial enzymes are characterized, and the tools used for identifying new bile acids become increasingly more sensitive, the repertoire of bile acids metabolized and/or synthesized by bacteria continues to grow. Additionally, bile acids impact microbiome community structure and function. In this Review, we highlight how the bile acid pool is manipulated by the gut microbiota, how it is dependent on the metabolic capacity of the bacterial community and how external factors, such as antibiotics and diet, shape bile acid composition. It is increasingly important to understand how bile acid signalling networks are affected in distinct organs where the bile acid composition differs, and how these networks impact infectious, metabolic and neoplastic diseases. These advances have enabled the development of therapeutics that target imbalances in microbiota-associated bile acid profiles.

Fig. 1 |. Enterohepatic circulation of bile acids in humans.

a | Primary bile acids (BAs) are synthesized from cholesterol in the liver by the classic (cholesterol 7α-hydroxylase (CYP7A1)-mediated) pathway or the alternative (sterol 27-hydroxylase (CYP27A1)-mediated) pathway. BA-CoA synthetase (BACS) and BA-CoA:amino acid N-acyltransferase (BAAT) then catalyse BA amidation (conjugation) with glycine or taurine to form bile salts. b | The gut microbiota metabolizes BAs secreted into the duodenum into secondary BAs. Reabsorption of approximately 95% of the BAs that reach the terminal ileum permits their recycling by the liver. CA, cholic acid; CDCA, chenodeoxycholic acid; CYP8B1, sterol 12α-hydroxylase.

Fig. 2 |. General bile acid structure.

Sites of dehydroxylation or oxidation (–H, –OH or =O) are indicated as R₁–R₄. Esterification and amidation or deconjugation occur at R₅.

Fig. 3 |. Factors affecting bacterial transformation of bile acids.

a | Dysbiosis or b | antibiotics reduce populations of 7α-dehydroxylating Firmicutes, and thereby perturb secondary bile acid (BA) levels. c | Dietary consumption of cholesterol increases total BA pools, but insoluble fibre can bind and sequester cholesterol and BAs in the intestinal lumen. Prebiotic fibre and other dietary components also modulate the microbiota composition. d | Exercise-associated shortened intestinal transit time reduces the concentrations of secondary BAs and reabsorption of BAs because they are excreted faster.

Fig. 4 |. Host and microbiota-dependent bile acid contributions to human disease.

a | Primary bile acids (BAs) promote Clostridioides germination, whereas secondary BAs inhibit it. Secondary BAs increase the efficacy of antimicrobials against C. difficile and sequester C. difficile toxins. b | Secondary BAs are associated with carcinogenesis through several mechanisms. Bacterially deconjugated taurine is further metabolized into carcinogenic hydrogen sulfide (H₂S). The insertion of secondary BAs into the plasma membrane triggers phospholipase A₂ (PLA₂) metabolism of phospholipids into arachidonic acid, ultimately leading to the release of DNA-damaging reactive oxygen species (ROS). Nuclear factor κB (NF-κB)-mediated expression of the pro-inflammatory cytokines IL-6 and IL-1β suppresses apoptosis through the JAK–STAT pathway and inhibits cell cycle arrest by p53, respectively. c | In enteroendocrine cells, TGR5 agonist BAs trigger synthesis of glucagon-like peptide 1 (GLP1), which circulates to pancreatic β-cells to induce insulin secretion. The presence of the gut microbiota has been separately associated with appetite regulation, energy harvest and insulin sensitivity. d | BA activation of PXR, FXR and monocyte TGR5 reduces inflammatory cytokine production and intestinal permeability by inhibiting NF-κB. CA, cholic acid; CDCA, chenodeoxycholic acid; C. scindens, Clostridium scindens; C. sordelli, Clostridium sordelli; DCA, deoxycholic acid; G-BA, glycine-conjugated bile acid; IBD, inflammatory bowel disease; LCA, lithocholic acid; PKC, protein kinase C; T-BA, taurine-conjugated bile acid.