Gut Microbial Metabolites on Host Immune Responses in Health and Disease

Abstract

Intestinal microorganisms interact with various immune cells and are involved in gut homeostasis and immune regulation. Although many studies have discussed the roles of the microorganisms themselves, interest in the effector function of their metabolites is increasing. The metabolic processes of these molecules provide important clues to the existence and function of gut microbes. The interrelationship between metabolites and T lymphocytes in particular plays a significant role in adaptive immune functions. Our current review focuses on 3 groups of metabolites: short-chain fatty acids, bile acids metabolites, and polyamines. We collated the findings of several studies on the transformation and production of these metabolites by gut microbes and explained their immunological roles. Specifically, we summarized the reports on changes in mucosal immune homeostasis represented by the Tregs and Th17 cells balance. The relationship between specific metabolites and diseases was also analyzed through latest studies. Thus, this review highlights microbial metabolites as the hidden treasure having potential diagnostic markers and therapeutic targets through a comprehensive understanding of the gut-immune interaction.

Keywords: Bile acids; Immunomodulation; Microbiota; Polyamines; Short-chain fatty acid.

Figure 1. The biosynthetic pathways of SCFAs, BAs and polyamines along with the microorganisms involved are presented. Acetate, propionate and butyrate, the 3 main components of SCFAs, are produced by microbial fermentation of dietary fiber. Acetate is produced from pyruvate through Wood-Ljungdahl pathway which mediates reduction from CO₂ to CO and subsequently converts acetyl-CoA and acetate. Propionate is synthesized through 3 different pathways: pyruvate is converted to succinate and lactate which finally forms propionate; propionate is generated via the propanediol pathway without passing through pyruvate; lactate from rumen microbial fermentation is converted to propionate through the acrylate pathway. Butyrate is synthesized by the formation of 2 molecules of acetyl-CoA, acetoacetyl-CoA, which is further converted to butyryl-CoA. In BA metabolism, cholesterol is converted to primary BAs, CA and CDCA, and conjugated with glycine or taurine in liver. After being secreted to the intestine, primary BAs are deconjugated through BSH produced by bacteria, such as Lactobacillus and Bifidobacterium. In the subsequent step, 7α/7β-dehydroxylation occurs and the product is oxidized and epimerized by 7α/7β-HSDH. In the polyamine biosynthetic pathway, Putrescine is generated by the decarboxylation of ornithine catalyzed by the enzyme ODC. The synthesis of spermidine and spermine is mediated by the enzyme AdoMetDC, and the transferase enzymes SpmdS and SpmS.

CYP7A1, cholesterol 7 alpha-hydroxylase; CYP27A1, sterol 27-hydroxylase; CYP8B1, sterol 12-alpha-hydroxylase; CYP7B1, 25-hydroxycholesterol 7-alpha-hydroxylase; BSH, bile salt hydrolase; ADC, arginine decarboxylase; AdoMet, S-adenosyl-methionine; DCAdoMet, decarboxylation product of S-adenosyl-methionine; AdoMetDC, adenosyl-methionine decarboxylase; SpmdS, Spermidine synthase.

Figure 2. Metabolite-mediated expansion of Treg and Th17 cells in the intestinal niche is depicted. SCFAs, converted from dietary fiber, pass from gut epithelium to laminal propria through passive diffusion and via transporters (SLC16a1, SLC5a8). Naïve T cells capture SCFAs through GPR43, which mediates inhibition of HDAC6/9 and the subsequent acetylation of the foxp3 promoter region, finally differentiating into Tregs. SCFAs also induce Th17 cell differentiation in inflammatory conditions such as Citrobacter rodentium infection. SCFAs directly inhibit HDAC3 without passing through GPR41 and GPR43, which subsequently increases mTOR activity and finally induces RORγt expression. IsoalloLCA promotes production of mitoROS and induces the acetylation of CNS3 region of FOXP3 promoter, resulting in the upregulation of FOXP3 transcription. IsoDCA acts on FXR on DC to repress pro-inflammatory activity and upregulate anti-inflammatory transcription factors like SOCS1 and IkBα which increases Tregs differentiation. The 3-oxoLCA directly interacts with RORγt to interfere in its transcriptional activity, resulting in the inhibition of Th17 cell differentiation. The polyamine spermidine directs the autophagy-mediated differentiation of Treg cells, thereby establishing a regulatory environment in the gut. Spermidine induces IDO1-dependent immunosuppressive phenotype in DCs and thus can promote the expansion of Treg cells. Spermine exhibits an anti-inflammatory effect by means of macrophage-mediated IL-10 production and suppression of IL-12 and IFN-γ production.

SLC16a1, monocarboxylate transporter 1; SLC5a8, sodium-coupled monocarboxylate transporter 1; RORγt, RAR-related orphan receptor gamma; SOCS1, suppressor of cytokine signaling 1; CNS3, conserved non-coding sequence 3; Atg5, autophagy protein 5; IDO1, indoleamine 2,3-dioxygenase 1.