Targeting the gut microbiota and its metabolites for type 2 diabetes mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia and insulin resistance. The incidence of T2DM is increasing globally, and a growing body of evidence suggests that gut microbiota dysbiosis may contribute to the development of this disease. Gut microbiota-derived metabolites, including bile acids, lipopolysaccharide, trimethylamine-N-oxide, tryptophan and indole derivatives, and short-chain fatty acids, have been shown to be involved in the pathogenesis of T2DM, playing a key role in the host-microbe crosstalk. This review aims to summarize the molecular links between gut microbiota-derived metabolites and the pathogenesis of T2DM. Additionally, we review the potential therapy and treatments for T2DM using probiotics, prebiotics, fecal microbiota transplantation and other methods to modulate gut microbiota and its metabolites. Clinical trials investigating the role of gut microbiota and its metabolites have been critically discussed. This review highlights that targeting the gut microbiota and its metabolites could be a potential therapeutic strategy for the prevention and treatment of T2DM.

Keywords: gut microbial metabolites; gut microbiota; probiotics; targeted therapy; type 2 diabetes mellitus.

Figure 1

The main mechanisms of SCFAs regulating metabolism and inflammation in T2DM. SCFAs are produced by the conversion of dietary fiber by gut microbiota and subsequently enter cells directly or act on transmembrane receptors such as FFAR2, FFAR3 and GPR109A, which are involved in improving T2DM related pathways, such as fatty acid oxidation, glucose metabolism and inflammation response. Meanwhile, SCFAs can inhibit the release of inflammatory factors such as TNF-α and IL-1β triggered by LPS through the NK-κB pathway, thus alleviating the inflammatory response. SCFAs, short-chain fatty acids; FFAR2, Free Fatty Acid Receptor 2; FFAR3, Free Fatty Acid Receptor 3; GPR109A, G-protein-coupled receptor 109A; TLR4, Toll-like receptor 4; LPS, Lipopolysaccharide; AMPK, Adenosine 5’-monophosphate (AMP)-activated protein kinase; cAMP, Cyclic adenosine monophosphate; PKA, protein kinase A system; HSL, hormone-sensitive lipase; FFA, free fatty acid; PGC-1α, Peroxisome proliferator-activated receptor-γ coactivator-1α; PPAR, peroxisome proliferator activated receptor; ATGL, Adipose triglyceride lipase; UCP1/2/3, uncoupling protein1/2/3; ATP, Adenosine triphosphate; IGN, intestinal gluconeogenesis; PYY, peotide YY; GLP-1, glucagon-like peptide-1; GLUT4, glucose transporter 4; HDACs, Histone Deacetylases; IL-10, Interleukin-10; IL-18, Interleukin-18; NF-κB, nuclear factor kappa-B; MAPK, mitogen-activated protein kinase; ERK1/2, extracellular regulated protein kinases; TNFα, Tumor necrosis factor α; IL-1β, Interleukin-1β; iNOS, Inducible nitric oxide synthase.

Figure 2

The main mechanisms of BAs regulating glucose homeostasis in T2DM. This figure illustrates the metabolism and transformation of bile acids in the liver, intestine, pancreas, and brown adipose tissue, and the mechanisms by which they regulate glucose homeostasis through the two major bile acid receptors, FXR and TGR5.CYP7A1, Cholesterol 7-alpha hydroxylase; CYP8B1, sterol 12α-hydroxylase; CA, cholic acid; CDCA, chenodeoxycholic acid; T/G, taurine/glycine; BSEP, bile salt export pump; SHP, small heterodimer; JNK/ERK, c-Jun N-terminal kinase/extracellular regulated protein kinases; FFGR4, FGF receptor 4; FGF19/15, fibroblast growth factor 19/15; ASBT, apical sodium-dependent bile acid transporter; PI3K, phosphatidylinositol-3-kinases; Akt, protein kinase B; mTOR, mammalian target of rapamycin; Cers,cermides;SREBP1, sterol-regulatory element binding proteins 1; FXR, farnesoid X receptor; NTCP, sodium taurocholate cotransporting polypeptide; OATP, Organic Anion Transporting Polypeptide; OSTα/β, organosolute transport proteins α and β; DCA, deoxycholic acid; LCA, lithic bile acids; TGR5, Takeda G protein-coupled receptor 5; cAMP, Cyclic adenosine monophosphate; DIO2, deiodinase type 2; T4, thyroxine; T3, triiodothyronine; GLP-1, glucagon-like peptide-1.

Figure 3

Role and mechanism of tryptophan metabolic pathway associated with T2DM. This figure depicts the conversion of tryptophan through the action of the gut microbiota, the products of which are involved in T2DM. ILA, indole-3-lactate; IPA, Indole 3-propionic acid;ILDH, indole-3-lactate dehydrogenase;ArAT Aromatic amino acid aminotransferase, IAld, indole-3-acetaldehyde; AhR, aryl hydrocarbon receptor; GLP-1, glucagon-like peptide-1.

Figure 4

Potential therapy and treatments for T2DM by regulating gut microbiota and its metabolites. Recent approaches to regulate gut microbiota for T2DM therapy focuses on probiotics, prebiotics, synbiotics, fecal microbial transplantation, diet intervention, bacteriophages, microbiota-targeted drugs and postbiotics. SCFAs, short-chain fatty acids; FMT, Fecal Microbiota Transplantation; BAs,bile acids; LPS, Lipopolysaccharide; IL-10, Interleukin-10; GLP-1, glucagon-like peptide-1; ZO-1, zonula occludens-1.