Gut microbiota metabolites, as the name suggests, are produced by the metabolism of the gut microbiota. The interaction of the gut microbiota with the host is often achieved through gut microbiota metabolites.
As far as the gut microbiota metabolites that have been identified so far are concerned, they can be broadly divided into three groups according to their ** and synthesis [1]:
1) metabolites produced by intestinal bacteria from dietary components;
2) metabolites produced by the host and modified by intestinal bacteria;
3) Metabolites resynthesized by intestinal bacteria.
Figure 1Production of gut microbiota-derived metabolites[1].
Dietary metabolites.
Food enters the gastrointestinal tract from the mouth, and undigested carbohydrates are fermented into short-chain fatty acids (SCFAS) through intestinal microbes.
SCFAS is the main metabolite of intestinal anaerobic bacteria fermentation [2], which can provide energy to different tissues, and can also regulate cell proliferation and differentiation, hormone secretion, and activation of immune-inflammatory responses. For example, propionic acid and butyric acid can inhibit stimulation-induced adhesion molecule expression and chemokine production, thereby inhibiting monocyte macrophage and neutrophil recruitment, and have anti-inflammatory effects[2].
Figure 2Effect of SCFA on host host performance[3].
Degradation of protein in the diet leads to the release of tryptophan, which can be converted into various catabolites by gut microbes. Among them, indole, IPA, and indoleacrylic acid (IA) can affect mucosal homeostasis by decreasing intestinal permeability; Indole also induces GLP-1 release from enteroendocrine L-cells. ILA, IAA, Skatole, etc., act on AHR in intestinal immune cells, thereby altering innate and adaptive immune responses in ligand-specific ways; Tryptamine stimulates gastrointestinal motility by inducing the release of 5-HT.
In addition, tryptophan catabolites are absorbed through the intestinal epithelium and enter the bloodstream, some of which (e.g., IPA, IE, IA) have antioxidant and anti-inflammatory effects, while indolephenol sulfate (IS) has cytotoxic effects at high concentrations[4].
Figure 3Mechanism of action of microbial tryptophan catabolites on host physiology[3]. Carnitine and choline compounds in animal foods can be metabolized to trimethylamine by the intestinal flora, which can then enter the liver and be oxidized by flavin monooxygenase to produce trimethylamine-n-oxide (TMAO) [5]. TMAO is a candidate risk factor for many chronic diseases [6].
Modification of host-produced metabolites.
After eating, the duodenum stimulates the gallbladder to contract, at which point the primary BAS synthesized and stored in the hepatocytes is excreted into the intestine. In the intestinal lumen, primary BAS can solubilize lipids, including cholesterol and fat-soluble vitamins. Approximately 95% of primary BAS is actively reabsorbed back into the liver via ASBT.
A small fraction of primary BAS escapes and reaches the colon, and the gut microbiota converts primary BAS into secondary BAS, a process involving three broad classes of bacterial enzymes, with major structural modifications including deconjugation, epimerization of hydroxyl groups, and debinding and dehydroxylation, leading to diversification of the BAS repertoire and affecting BAS signaling [7].
Figure 4Hepatic BA synthesis, enterohepatic circulation, and microbial BA modification in vivo[7].
ba: bile acid; ca: cholic acid; cdca: chenodeoxycholic acid; dca: deoxycholic acid; udca: ursodeoxycholic acid; lca : lithocholic acid; tca: taurocholic acid; gca: glycocholic acid; c: cholesterol; bsep : bile salt-export pump; ntcp: na+-taurocholic acid co-transporting polypeptide; asbt : apical sodium-dependent ba transporter; ostα/β: organic solute transporter α/β; bsh: bile salt hydrolases; hsdh : hydroxysteroid dehydrogenase; bai : ba inducible genes.
Self-synthesized metabolites.
The gut microbiota itself can also synthesize metabolites such as (1) branched-chain amino acids (BCAAs), which promote protein synthesis and provide energy. (2) Polyamines, which can bind to proteins and nucleic acids to regulate cell growth. and (3) vitamins, which are further utilized in the colon [1]. These 3 types of substances synthesized by the intestinal flora themselves can also be obtained by the human body through diet.
Gut microbiota metabolites and tumor immunity.
Studies have shown that 70% of immune cells live in the gut, and gut microbiota-derived metabolites continue to regulate local and systemic immune cells[1]. For example, increasing intestinal butyric acid levels promotes IL-22 production in ILCS and CD4+ T cells[8]. Tryptophan metabolites such as IE significantly inhibit NF-B and IL-10R expression[9]. and lithocholic acid can reduce the levels of IL-1, TNF-, caspase-1, and IL-22 [10].
Figure 5Gut microbiota-derived metabolites regulate host immune responses[1].
a) effects of gut microbiota-derived metabolites on B cells, macrophages, and dendritic cells; and (b) Effects of gut microbiota-derived metabolites on T cells.
Tumor immunity has always been closely linked, and some microbial metabolites can regulate the anti-tumor efficacy of chemotherapy and immunity** by shaping host immunity, thereby affecting the development of cancer.
Xiaohuan Guo's research group at the Institute of Immunology, Tsinghua University School of Medicine, found that the intestinal microbiota increases the expression of ID2 in CD8+ T cells and enhances the anti-tumor immune response of CD8+ T cells through its metabolite short-chain fatty acid butyric acid, thereby improving the anti-tumor effect** [11].
Figure 6Gut microbial metabolites promote anticancer** effects by modulating cytotoxic CD8+ T cell immunity[11]. Maik Luu et al injected B16ova melanoma cells subcutaneously into CD45In 2+ mice, valeric acid and butyric acid were found to enhance the antitumor activity of cytotoxic T-lymphocytes (CTLs) through metabolic and epigenetic reprogramming [12]. In addition, the tryptophan metabolite, indoleacetic acid, can also improve the chemotherapy efficacy in mice with pancreatic ductal adenocarcinoma [13].
In this issue, we introduce the metabolites of intestinal microbiota that have been studied more in China in recent years, their classification and composition, and their correlation with tumor immunity. I hope that everyone can have a basic understanding of the metabolites of intestinal flora, and those who need it can also like and collect it
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