Gut microbiota-derived metabolites as central regulators in metabolic disorders

Abstract

Metabolic disorders represent a growing worldwide health challenge due to their dramatically increasing prevalence. The gut microbiota is a crucial actor that can interact with the host by the production of a diverse reservoir of metabolites, from exogenous dietary substrates or endogenous host compounds. Metabolic disorders are associated with alterations in the composition and function of the gut microbiota. Specific classes of microbiota-derived metabolites, notably bile acids, short-chain fatty acids, branched-chain amino acids, trimethylamine N-oxide, tryptophan and indole derivatives, have been implicated in the pathogenesis of metabolic disorders. This review aims to define the key classes of microbiota-derived metabolites that are altered in metabolic diseases and their role in pathogenesis. They represent potential biomarkers for early diagnosis and prognosis as well as promising targets for the development of novel therapeutic tools for metabolic disorders.

Keywords: bile acid metabolism; intestinal microbiology; obesity.

Figure 1

Bile acid (BA) dysmetabolism in metabolic syndrome. BA metabolism is altered in patients with metabolic syndrome (MetS) and is associated with hepatic steatosis and glucose and lipid dysmetabolism. Dietary animal fat consumption promotes taurocholic acid (TCA) production, which favours the proliferation of sulfite-reducing bacteria, Bilophila wadsworthia, leading to an increase in intestinal permeability and inflammation (panel 1). Gut microbiota alterations induce an impairment in the ileal absorption of BAs, which occurs normally via the apical-sodium BA transporter (ASBT). This induces a decrease in the expression of nuclear Farnesoid-X receptor (FXR) and fibroblast growth factor 19 (FGF19) in intestinal epithelial cells and the abundance of colonic primary conjugated BAs (panel 2). Gut microbiota dysfunction leads to a decreased transformation of primary conjugated BAs to secondary BAs in the colon, leading to defective activation of Takeda-G-protein-receptor-5 (TGR5). The effect of TGR5 activation on the increase in glucagon-like peptide 1 (GLP-1) and white adipose tissue (WAT) browning was thus inhibited (panel 3). Gut microbiota alterations impair bile salt hydrolase (BSH) activity, leading to primary conjugated BA accumulation in the colon (panel 4). BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

Figure 2

Short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs) and Trimethylamine N-oxide (TMAO): relevant effects for metabolic syndrome on the host. Microbiota-derived metabolites mediate diverse effects on host metabolism. SCFAs (green frame): (i) increase satiety and browning of white adipose tissue (WAT); (ii) induce a decrease in lipogenesis and associated inflammation; (iii) increase the secretion of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) and (iv) participate in the maintenance of intestinal barrier integrity. BCAAs (yellow frame): (i) increase thermogenesis, protein synthesis and hepatocyte proliferation but (ii) are also associated with insulin resistance and visceral fat accumulation. TMAO (red frame): increases cardiovascular risks by inducing hyperlipidaemia, oxidative stress and pro-inflammatory cytokines.

Figure 3

Tryptophan metabolism alterations in metabolic syndrome. Tryptophan dysmetabolism is associated with liver inflammation, steatosis and insulin resistance. In metabolic syndrome (MetS), the inflammatory state is associated with kynurenine (KYN) production through the activation of indoleamine 2,3-dioxygenase 1 (IDO1). This leads to an increase in kynurenine-derived metabolites, such as kynurenic acid (KYNA), xanthurenic acid (XA), 3-hydroxykynurenine (3-H-KYN), 3-hydroxyanthranilic acid (3-HAA) and quinolinic acid (QA). In parallel, the gut microbiota presents a defect in the production of aryl hydrocarbon receptor (AhR) ligands such as indole-3-propionic acid (IPA). The incretin hormone glucagon-like peptide 1 (GLP-1) secretion from intestinal enteroendocrine L cells and interleukin (IL)-22 production are decreased, altering gut permeability and promoting lipopolysaccharide (LPS) translocation. Serotonin (5-HT) biosynthesis from intestinal enterochromaffin cells is also reduced in the context of MetS due to a decrease in the production of microbiota-derived metabolites inducing the production of host 5-HT.