Gut Microbiota and Metabolites: Biomarkers and Therapeutic Targets for Diabetes Mellitus and Its Complications

Abstract

Diabetes mellitus (DM) is a complex metabolic disease characterized by significantly elevated blood glucose levels as a result of dysfunctional or impaired pancreatic β-cells, leading to insulin deficiency. This condition can result in severe complications, including cardiovascular diseases, kidney failure, vision impairment, and nerve damage. Currently available anti-diabetic drugs do not fully prevent the progression of these complications. Moreover, they often have significant side effects. The gut microbiota plays a crucial role in influencing diet, energy metabolism, and blood glucose levels. Research shows a strong link between microbiota dysbiosis and DM, as well as the severity of its complications. Commensal bacteria can help manage blood glucose levels, reduce inflammation, regulate metabolism, and enhance the gut barrier. Conversely, opportunistic pathogens can worsen insulin resistance, promote metabolic disorders, disrupt gut integrity, and affect appetite and weight. This article describes the characteristics of gut microbiota in various types of DM and explores the role of the "gut microbiota-metabolite-signaling pathway" axis in DM and its complications. In addition, it highlights the therapeutic potential of traditional Chinese medicine and dietary interventions through modulation of the gut microbiota and metabolites. The aim is to provide comprehensive evidence supporting the integration of TCM dietary therapy, targeted dietary strategies, and specific probiotics as alternative and complementary therapies for DM and its complications.

Keywords: diabetes mellitus; diabetic complications; diets; gut microbiota; traditional Chinese medicine.

Figure 1

The gut microbiota in different types of DM regulates blood glucose levels by modulating the expression of metabolites. The differences in microbial community abundance, as shown in the figure, may be key factors for distinguishing between types of DM. These microbial communities influence the host’s metabolic profile, affecting glucose and lipid metabolism, and contributing to the onset and progression of the disease. T1DM, Type 1 diabetes mellitus. T2DM, Type 2 diabetes mellitus. GDM, Gestational diabetes mellitus. SCFAs, Short-chain fatty acids. BCAAs, Branched-chain amino acids. FFA, Free fatty acid. 2-HB, 2-Hydroxybutyrate. DAG, Diacylglycerol. AGEs, Glycation end-products. GABA, Gamma aminobutyric acid. GLP-1, Glucagon-like peptide-1. GIP, Glucose-dependent insulin-dependent polypeptide.

Figure 2

The gut microbiota plays a key role in the synthesis and metabolism of metabolites. As shown in the figure, the microbial community regulates the levels of specific metabolites, targeting one or more metabolites to influence the host’s metabolic balance. SCFAs, Short-chain fatty acids. BCAAs, Branched-chain amino acids.

Figure 3

Metabolites’ involvement in DM and its complications through the regulation of signaling pathways. Metabolites such as BCAAs, ginsenosides, and IPA modulate signaling pathways including AMPK, Akt, and ROS, thereby influencing the onset and progression of various diseases. BCAAs, Branched-chain amino acids. G-Rk3, Ginsenoside Rk3. EPA, Eicosapentaenoic Acid. IPA, Indolepropionic acid. G-Rg5, Ginsenoside Rg5. G-RD, Ginsenoside Rd. G-Rg3, Ginsenoside Rg3. G-Rb1, Ginsenoside Rb1.

Figure 4

Metabolites like SCFAs, EPA, leucine, and lupeol play significant roles in the development of DM and its complications by regulating key signaling pathways, including NF-κB, AMPK, and mTOR. These pathways are essential for maintaining metabolic homeostasis. EPA, Eicosapentaenoic Acid. SCFAs, short-chain fatty acids.

Figure 5

Different dietary structures and eating habits have a regulatory effect on the gut microbiota. A diet rich in vegetables, high in fiber, and low in sugar can promote the abundance of beneficial bacteria, while an HF diet can increase the abundance of pathogenic bacteria. MedDiet, Mediterranean diet. TRE, Time-restricted eating. RF, Ramadan fasting. CDHFD, Cold drink and high-fat diet. HF, High-fat. HS, High-sucrose.

Figure 6

Different dietary structures affect the gut microbiota and metabolism and regulate blood glucose. In the diagram, arrows represent regulatory effects, and different background colors represent the direct impact of dietary structure on the gut microbiota. Reasonable diet on the left side and balanced gut, blood glucose homeostasis. In contrast, the right side indicates that poor dietary habits lead to gut homeostasis imbalance and opportunistic pathogens. Subsequently, under the influence of the microbiota, the body’s metabolism changes its function, thereby participating in blood glucose regulation. LPSs, Lipopolysaccharides. SCFAs, Short-chain fatty acids. BCAAs, Branched-chain amino acids. FFAs, Free fatty acids. GABA, Gamma aminobutyric acid. IPA, Indolepropionic acid. TMAO, Trimethylamine N-oxide. MedDiet, Mediterranean diet. TRE, Time-restricted eating. CDHFD, Cold drink and high-fat diet. HF, High-fat. HS, High-sucrose. HFD, High-fiber diet. RS, resistant starch. n-3 PUFA, Omega-3 polyunsaturated fatty acids.