Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis

Abstract

Inflammatory bowel disease (IBD) and colorectal cancer (CRC) are heterogeneous intestinal diseases that threaten the health of an increasing number of individuals as their lifestyles become westernized. New insights have been discovered with the development of various omics techniques, revealing that gut-microbiota-derived metabolites play important roles in maintaining intestinal homeostasis and modulating the progression of intestinal diseases from both metabolic and immunological perspectives. Clinical metagenomic and metabolomic studies have revealed links between microbial bile acid (BA) metabolism and IBD and CRC progression. Several BA-derived metabolites were recently been demonstrated to play a role in intestinal immunity, providing fresh insights into how BAs affect the course of IBD and CRC. In this review, we discuss recent studies on the involvement of gut microbiota-derived BAs in intestinal immunity, inflammation, and tumorigenesis along with human omics data to provide prospective insights into future prevention and treatment of IBD and CRC.

Keywords: bile acids; colorectal cancer; gut microbiota; inflammatory bowel diseases; omics.

Figure 1. Gut Microbiota Regulates BA Metabolism in the Enterohepatic Circulation.

BAs are synthesized from cholesterol in the liver via oxidation catalyzed by cytochromes P450 (CYPs) and conjugation catalyzed by bile acid-CoA synthetase (BACS) and bile acid-CoA: amino acid N-acyltransferase (BAAT). Subsequently, BAs are secreted into intestine post prandial. Most BAs (90–95%) are reabsorbed into liver by portal vein blood and only a small portion (5–10%) are excreted into feces. Gut microbiota inhabiting the intestines carry out biotransformations to convert primary bile acids (PBAs) into secondary bile acids (SBAs) and convert conjugated BAs into unconjugated BAs. Major microbial biotransformation reactions include deconjugation mediated by bile salt hydrolases (BSH), 7α/β-dehydroxylation mediated by bai genes, and oxidation and epimerization mediated by hydroxysteroid dehydrogenases (HSDH).

Figure 2. Gut Microbiota-derived BAs Regulate Immune Response in Colon.

(A) Bacterial epimerization and isomerization generate distinct BAs derivatives. 3-Oxodeoxycholic acid (DCA)/lithocholic acid (LCA) is generated from DCA/LCA, and isoDCA/LCA is generated by 3-oxoDCA/LCA by the actions of 3α-HSDH and 3β-HSDH respectively. Furthermore, allo-, 3-oxoallo-, isoalloLCA are produced by the cooperation of 5α/β-reductase (5AR/BR) and 3α/β-HSDH. (B) BA metabolites control colon T cell differentiation and dendritic cell (DC) activity. 3-OxoLCA binds to retinoic acid receptor-related orphan receptor γt (RORγt) and directly inhibits the differentiation of T helper 17 (T_H17) cells, while isoalloLCA enhances the differentiation of anti-inflammatory regulatory T (T_reg) cells by inducing production of mitochondrial reactive oxygen species and increasing binding of nuclear hormone receptor NR4A1 at the Foxp3 locus, leading to enhanced Foxp3 gene transcription. Moreover, isoDCA inhibits immunostimulatory properties of DC dependent on farnesoid X receptor (FXR), resulting in the expansion of peripheral T_reg cells. (C) In small intestine lamina propria CD4⁺ T effector (T_eff) cells, the nuclear receptor constitutive androstane receptor (CAR) regulates multidrug resistance protein 1(Mdr1) expression and induces anti-inflammatory cytokine interleukin 10 (IL-10) to detoxify BAs exposure in the lumen. VDR, vitamin D receptor.

Figure 3. BA Receptors in IBD and CRC.

(A) G protein-coupled receptor 1 (TGR5) activation by secondary bile acids (SBAs) drive intestinal epithelium regeneration and prevents intestinal inflammation. Primary BAs (PBAs) are biotransformed to SBA via a series of gut microbiota-mediated reactions. Microbial dysbiosis disrupts biotransformation and alters the composition of intestinal BA pool, leading to colitis occurrence and progression. In intestinal stem cells (ISCs), TGR5 activation activates SRC/yes-associated protein 1 (YAP) signaling, triggering ISC renewal and proliferation. In macrophage, TGR5 activation blocks NLRP3 inflammasome phosphorylation and ubiquitination, thus inhibiting intestinal inflammation. Therefore, deoxycholic acid (DCA)/lithocholic acid (LCA) supplementation promotes ISCs stemness and inhibits NLRP3 inflammasome activity, alleviating colitis occurrence. (B) BA receptors FXR and TGR5 are activated by BA derivatives or other agonists, stimulating targeted pathways to regulate intestinal stemness, inflammation and tumorigenesis. FXR activation reshapes the BA profiles, antagonizes Wnt/β-catenin signaling and suppresses transactivation of suppressor of cytokine signaling 3 (SOCS3) gene, thus curtailing CRC progression. TGR5 activation by UDCA suppresses YAP signaling, which inhibits cell proliferation and malignant tumor progression. CDCA, chenodeoxycholic acid; Fex, fexaramine; UDCA, ursodeoxycholic acid.