The role of intestinal microbes on intestinal barrier function and host immunity from a metabolite perspective

Abstract

The gut is colonized by many commensal microorganisms, and the diversity and metabolic patterns of microorganisms profoundly influence the intestinal health. These microbial imbalances can lead to disorders such as inflammatory bowel disease (IBD). Microorganisms produce byproducts that act as signaling molecules, triggering the immune system in the gut mucosa and controlling inflammation. For example, metabolites like short-chain fatty acids (SCFA) and secondary bile acids can release inflammatory-mediated signals by binding to specific receptors. These metabolites indirectly affect host health and intestinal immunity by interacting with the intestinal epithelial and mucosal immune cells. Moreover, Tryptophan-derived metabolites also play a role in governing the immune response by binding to aromatic hydrocarbon receptors (AHR) located on the intestinal mucosa, enhancing the intestinal epithelial barrier. Dietary-derived indoles, which are synthetic precursors of AHR ligands, work together with SCFA and secondary bile acids to reduce stress on the intestinal epithelium and regulate inflammation. This review highlights the interaction between gut microbial metabolites and the intestinal immune system, as well as the crosstalk of dietary fiber intake in improving the host microbial metabolism and its beneficial effects on the organism.

Keywords: AHR; dietary fibre; intestinal microorganisms; short-chain fatty acids; tryptophan.

Figure 1

Production of microbial metabolites in the gut. (A) Obtained from food. Microorganisms in the colon and cecum produce short-chain fatty acids by fermentation of undigested dietary fibre. Tryptophan-derived metabolites are derived from the direct conversion of tryptophan by gut microbes. (B) Synthesis of intestinal bacteria from scratch. Primary bile acids are produced in the liver, transported to the gut and then produced as secondary bile acids by the action of gut microbes.

Figure 2

The role of intestinal microbial metabolites in the intestinal immune barrier. (1) Low ester pectin, a product of dietary fiber, binds to Toll like receptor 2 (TLR2) and suppresses TLR2 receptor activation, hence lowering NF-κB (Nuclear transcription factor-κB) activity. SCFA are produced by gut microbes in response to dietary fiber stimulation, and these fatty acids stop histone deacetylases and pro-inflammatory mediators caused by NF-κB. (2) Intestinal microbial-derived tryptophan metabolites, indoles maintain normal intestinal epithelial function via the pregnane X receptor (PXR), and tryptophan metabolites are AHR ligands in innate lymphocytes that act with the AHR via transcription factors to stimulate IL-22 (Interleukin-22) expression. Antimicrobial peptides promote expression through IL-22 and enhance mucin proliferation in goblet cells. (3) Bacterial bile acid metabolites affect intestinal immunity in different ways, with secondary bile acids binding to FXR (Farnesoid X receptor) to protect intestinal integrity.

Figure 3

BA metabolism affects host immunity. (1) In the classical pathway, CYP7A1 converts cholesterol to 7α-hydroxy-cholesterol, which is then further converted to hydroxy-4-cholesten-3-one through the action of Steroid dehydrogenase. Another enzyme, CYP8B1, hydroxylates hydroxy-4-cholesten-3-one to produce CA. CA binds to taurine, resulting in the formation of TCA. (2) In the alternative pathway, cholesterol is converted to 27-hydroxycholesterol by CYP27A1, followed by the production of CDCA through the action of CYP7B1. CDCA then binds to glycine to form GCDCA. Both TCA and GCDCA are transported through the bile to the intestine, where they undergo dehydroxylation and deamination by microorganisms. This microbial action leads to the production of secondary bile acids, LCA, and DCA. LCA and DCA interact with TGR5 and FXR present on macrophages and dendritic cells, leading to the inhibition of pro-inflammatory factor secretion. Furthermore, these bile acids play a crucial role in maintaining intestinal epithelial barrier function and exert immunoprotective effects. CYP8B1, sterol 12α-hydroxylase; CA, cholic acid; CDCA, chenodeoxycholic acid; TCA, taurocholic acid; GCDCA, glycochenodeoxycholic acid; LCA, lithocholic acid; DCA, deoxycholic acid.

Figure 4

Synthesis and degradation of serotonin in enterochromaffin cells. Serotonin (5-HT) is synthesized by enterochromaffin cells (purple) in the GI tract from L-tryptophan via the rate-limiting enzyme TPH-1.L-5-hydroxytryptophan is then converted into active 5-HT by L-aromatic acid decarboxylase (L-AADC) and stored in enterochromaffin granules. Apically, enterochromaffin cells are stimulated to secrete 5-HT by GPCR in the colon and by glucose-dependent in-sulinotropic peptide-1 in the small intestine, while 5-HT4R inhibits 5-HT release. Basolaterally, EC cells express muscarinic,adrenergic, and 5-HT3 receptors, activation of which leads to 5-HT release, while activation of GABAA, nicotinic, somatostatin-R2,and 5-HT4R inhibit 5-HT release. enterochromaffin cells or enterocytes (orange) can uptake 5-HT via the serotonin reuptake transporter (SERT)and degrade 5-HT to 5-hydroxindole acetic acid via enzyme MAO (R, receptors).

Figure 5

Effects of tryptophan-derived metabolites on host immunity. Tryptophan-derived metabolites can be produced through the direct conversion of tryptophan by gut microbes. One such metabolite, 3-HAA, inhibits the PI3K/AKT/mTOR and NF-κB signaling pathways, leading to reduced production of pro-inflammatory factors IL-6 and TNF-α in macrophages. Another metabolite, IPA, activates PXR and AHR, playing a crucial role in regulating intestinal barrier function. Moreover, tryptophan-derived metabolites also impact T cells by releasing TGFβ, IL-10, and IL-35, which contribute to the suppression of tissue inflammation. Indole, another metabolite, modulates GLP-1 secretion in colonic enteroendocrine cells, thereby stimulating insulin secretion from pancreatic β cells. 3-HAA, 3-Hydroxyanthranilic acid. TGFβ, Transforming growth factor-β.

Figure 6

The cellular AHR signaling pathway. Normally, AHR exists in a dormant state within the cytoplasm, bound to a complex of HSP90, XAP2 (X-Associated Protein-2, also known as ARA9 and AIP), and HSP90 Co-chaperonep23. However, upon ligand binding, AHR undergoes a conformational change that exposes a NLS, leading to the release of HSP90 from the complex. This allows the activated AHR to translocate into the nucleus, where it forms a hetero-dimer with the ARNT. Together, the AHR-ARNT heterodimer binds to the XRE of target genes, inducing the expression of genes like IL-22, CYP1A1, CYP1A2, and CYP1B1.