Gut Microbiota: An Important Player in Type 2 Diabetes Mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is one of the common metabolic diseases in the world. Due to the rise in morbidity and mortality, it has become a global health problem. To date, T2DM still cannot be cured, and its intervention measures mainly focus on glucose control as well as the prevention and treatment of related complications. Interestingly, the gut microbiota plays an important role in the development of metabolic diseases, especially T2DM. In this review, we introduce the characteristics of the gut microbiota in T2DM population, T2DM animal models, and diabetic complications. In addition, we describe the molecular mechanisms linking host and the gut microbiota in T2DM, including the host molecules that induce gut microbiota dysbiosis, immune and inflammatory responses, and gut microbial metabolites involved in pathogenesis. These findings suggest that we can treat T2DM and its complications by remodeling the gut microbiota through interventions such as drugs, probiotics, prebiotics, fecal microbiota transplantation (FMT) and diets.

Keywords: glucose metabolism; gut microbiota; insulin resistance; pathogenesis; type 2 diabetes mellitus.

Figure 1

The association between the gut microbiota and T2DM. Dysbiosis of the gut microbiota has been demonstrated not only in T2DM populations, but also in certain animal models, including mice, cats and zebrafish. Furthermore, the gut microbiota is closely associated with various diabetic complications, such as diabetic nephropathy, diabetes-induced cognitive impairment, diabetic retinopathy, and diabetic peripheral neuropathy.

Figure 2

Dysregulated host molecules change the composition of the gut microbiota and thus contribute to the development of T2DM. Deletion of Sirtuin 1, ZnT8, FXR, Timp3, IL-36, TRIM31 and NABE-PLD, as well as overexpression of mTORC1, MGLL, ANGPTL4 and GLUT2, induce gut microbiota dysbiosis. ZnT8, Zinc transporter 8; FXR, Farnesoid X receptor; Timp3, Tissue inhibitor of metalloproteinase 3; IL-36, Interleukin 36; TRIM31, Tripartite motif-containing protein 31; NAPE-PLD, N-acylphosphatidylethanolamine phospholipase D; mTORC1, Mechanistic target of rapamycin complex 1; MGLL, Monoglyceride lipase; ANGPTL4, Angiopoietin-like 4; GLUT2, Glucose transporter 2.

Figure 3

Immune and inflammatory responses induced by the gut microbiota in T2DM. (A) The intestinal barrier is disturbed in T2DM. Hyperglycemia disrupts the integrity of tight and adherent junctions by GLUT2. F. prausnitzii abundance and its metabolite MAM levels are downregulated in db/db mice, which results in damaged intestinal barrier by reducing ZO-1 expression. Analogously, A. muciniphila abundance and the levels of A. muciniphila-derived EVs and Amuc_1100 are reduced in diabetic mice, which also disrupts intestinal barrier integrity. The increased intestinal permeability leads to the translocation of bacteria and bacterial products, which not only activates the innate immunity and inflammation in the gut, but also causes metabolic endotoxemia and systemic inflammation. (B) Multiple immune cells are involved in the influence of the gut microbiota on host metabolism. Lack of IL-17 receptor promotes intestinal dysbiosis and LPS translocation into visceral adipose tissue by inhibiting the migration of neutrophils in the intestinal mucosa. Reduced liver CRIg⁺ macrophages leads to an accumulation of EVs containing gut microbial DNAs in obesity, thereby promoting tissue inflammation and insulin resistance. The number of T_H17 cells is reduced in the intestinal tissues of obese mice, which leads to metabolic disorders by regulating the functions of Paneth cells. Furthermore, HFD-fed mice show a decrease in IgA⁺ immune cell percentage and secretory IgA concentrations in colon tissues, which impairs glucose metabolism by increasing intestinal permeability and changing microbial composition. GLUT2, Glucose transporter 2; MAM, Microbial anti-inflammatory molecule; ZO-1, Zonula occludens-1; EVs, Extracellular vesicles; PRRs, Pattern recognition receptors; IL-17, Interleukin 17; LPS, Lipopolysaccharide; CRIg, Complement receptor of the immunoglobulin superfamily.

Figure 4

Molecular mechanisms of gut microbial metabolites involved in T2DM. Various gut microbial metabolites, including SCFAs, bile acids, BCAAs, tryptophan-derived metabolites, TMAO, succinate, imidazole propionate, N-formyl peptide and isovanillic acid 3-O-sulfate, contribute to the development of T2DM through complex molecular mechanisms. SCFAs, Short chain fatty acids; BCAAs, Branched-chain amino acids; TMAO, Trimethylamine N-oxide; GPR43, G protein-coupled receptor 43; FOXO1, Forkhead box O1; GLP-1, Glucagon-like peptide-1; PYY, Peptide YY; HDAC5, Histone deacetylase-5; PCSK9, Proprotein convertase subtilisin/kexin type 9; TGR5, Takeda G-protein receptor 5; cAMP, Cyclic AMP; D2, Type 2 iodothyronine deiodinase; FGF21, Fibroblast growth factor 21; UCP1, Uncoupling protein 1; BCKAs, Branched-chain α-keto acids; mTORC1, Mechanistic target of rapamycin complex 1; GLUT4, Glucose transporter 4; PI3K, Phosphoinositide 3-kinase.

Figure 5

Various antidiabetic interventions targeting the gut microbiota. Probiotics and prebiotics, TCM and natural compounds, as well as certain non-drug therapies, such as bariatric surgery, FMT, diets, and exercise, can reshape the gut microbiota to treat T2DM. TCM, Traditional Chinese medicine; FMT, Fecal microbiota transplantation.