The interaction mechanism between type II diabetes and gut microbiota.

Diabetes mellitus (DM) is a chronic metabolic disease, classified into type I diabetes (T1DM) and type II diabetes (T2DM) based on its pathogenesis. Type I diabetes is categorized as an autoimmune disease; type II diabetes is a metabolic syndrome characterized by absolute or relative insulin deficiency and reduced sensitivity of target organs to insulin. Most diabetes patients have type II diabetes.

In recent years, there have been significant differences in the abundance of the microbiota, intestinal barrier, and intestinal metabolites between diabetic subjects and normal subjects. To further understand the relationship between diabetes and gut microbiota, this article reviews the interaction mechanisms between type II diabetes and gut microbiota.

1. Gut Microbial Composition and Diabetes
The concentration, proportion, and function of gut microbiota in patients with type II diabetes differ from those in healthy subjects.
In a study involving 36 adult subjects, the level of Bifidobacterium was higher in healthy populations, while the level of Lactobacillus was significantly increased in type II diabetes patients. Additionally, the study reported a reduction in the levels of Fusobacterium and Akkermansia in the intestines of type II diabetes patients compared to healthy subjects.
Huang et al. reported that when blood sugar levels rise, the level of Enterococcus increases, while the levels of Bifidobacterium and other Bifidobacteria decrease, further exacerbating diabetes. Some opportunistic pathogens, such as Bacteroides, Escherichia coli, and Desulfovibrio, were also found to be significantly increased in the intestines of diabetes patients.
He et al. found that Bacteroides was negatively correlated with type II diabetes. The levels of Bacteroides, Bifidobacterium, and Enterobacterium decreased in type II diabetes patients.

2. Gut Microbiota Metabolites and Diabetes
The gut microbiota is considered a metabolic organ that produces a large number of metabolites (short-chain fatty acids, bile acids, indole derivatives, etc.), which signal through their homologous receptors to regulate the host's metabolism.
(1) Short-chain fatty acids (SCFAs)
Previous studies have reported a reduction in bacteria that produce short-chain fatty acids in diabetes patients, leading to decreased production of SCFAs. These reduced SCFAs can affect the upregulated intestinal anti-inflammatory response and weaken the activation of short-chain fatty acid receptors. Short-chain fatty acid receptors belong to the G-protein-coupled receptor (GPCR) family, including GPR41 and GPR43, which, when activated by SCFAs, play important physiological roles in fat metabolism, glucose metabolism, and peptide YY (PYY) production, regulating intestinal motility and nutrient absorption.
In addition, dysbiosis can also weaken the function of GPR43, particularly in regulating the fat-insulin signaling pathway, leading to reduced energy expenditure and decreased insulin secretion.
Among various short-chain fatty acids, butyrate has received particular attention. Some studies suggest that impaired glucose metabolism is associated with a decrease in the levels of butyrate-producing bacteria in diabetes patients. Butyrate can regulate the size and function of the colonic regulatory T cell pool by stimulating the secretion of glucagon-like peptide-1 (GLP-1), enhancing insulin sensitivity and reducing the inflammatory response in adipocytes.
(2) Bile acids
Bile acids, as signaling molecules that control glucose homeostasis, are produced by hepatocytes and secreted into the intestine to promote the absorption of dietary lipids. Bile acids can effectively increase the proportion of beneficial bacteria such as Lactobacillus in diabetes patients and reduce the levels of opportunistic pathogens such as Escherichia coli and Salmonella.
The gut microbiota metabolizes primary bile acids into secondary bile acids through bile salts and 7α-dehydroxylase. When bile acid receptors are activated, they activate a series of nuclear receptors that regulate the secretion of the gut incretin hormone GLP-1, reduce gluconeogenesis, increase energy expenditure, stimulate pancreatic insulin secretion, and alleviate inflammation in immune cells.

3. Intestinal Barrier and Immunity
The intestinal barrier consists of the intestinal epithelial barrier, the intestinal mucus barrier, and the intestinal vascular barrier. Immune cells in the lamina propria of the intestinal epithelium, such as dendritic cells, Paneth cells, lymphocytes, and macrophages, can secrete various antimicrobial IgG, peptides, and cytokines to maintain intestinal immune homeostasis.
If the integrity of the intestinal barrier is compromised, severe systemic inflammation and metabolic diseases can occur. Lipopolysaccharides (LPS) can cross the intestinal epithelial barrier through intestinal leakage or chylomicrons. The inflammatory response in diabetes patients may be related to the increased levels of LPS caused by increased intestinal permeability.
In addition, the host's innate immune system plays a role in the relationship between gut microbiota and diabetes.
Myeloid differentiation factor 88 (MyD88) is a downstream target of most TLRs and IL-1 receptor-mediated signaling pathways, playing an important role in innate immune signaling. It has been reported that liver-specific deletion of MyD88 can make mice prone to glucose intolerance, inflammation, hepatic insulin resistance, and induce changes in the gut microbiota. Additionally, pro-inflammatory cytokines, such as monocyte chemoattractant protein-1 (MCP-1) and interferon-gamma (INF-γ), are also associated with the occurrence of type II diabetes.
Therefore, the impairment of intestinal barrier integrity and autoimmune imbalance both affect the occurrence of diabetes to varying degrees.
4. Gut Hormones, Gut Microbiota, and Diabetes

Gut hormones are produced and secreted by enteroendocrine cells (EECs). The function of EECs is regulated by the gut microbiota, and the composition and diversity of the gut microbiota greatly influence the release of gut hormones, including cholecystokinin (CCK), peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and gastric inhibitory peptide.
GLP-1 and PYY are secreted by intestinal endocrine L cells. They promote satiety and inhibit energy intake. GLP-1 is mainly released under the influence of carbohydrates and fats. Gut hormones (GLP-1, P substance, adiponectin, and leptin) may be directly or indirectly related to the occurrence of diabetes. Serum adiponectin levels in patients with type II diabetes are significantly lower than those in healthy populations.
The interaction mechanism between gut microbiota and diabetes is shown in Figure 1.

Figure 1 Interaction mechanism between gut microbiota and diabetes.

PYY, peptide tyrosine tyrosine; GLP-1, glucagon-like peptide-1; GPR G, G protein-coupled receptor; INF-γ, interferon gamma; IL, interleukin; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein 1; SCFAs, short-chain fatty acids; TL, Toll-like receptor.
V. Gut microbiota, mTOR, and diabetes.
Mammalian target of rapamycin (mTOR) is an important regulatory factor for cell growth and proliferation.
Mammalian target of rapamycin complex 1 (mTORC1) can promote anabolic processes such as protein and lipid biosynthesis, and it also inhibits catabolic processes such as autophagy. Its activity is regulated by growth factors, insulin, and energy availability (AMP/ATP ratio). Its excessive activation can lead to diabetes, inflammation, and neurodegenerative diseases.
Metabolites secreted by the microbiota, such as SCFAs, regulate many host functions, primarily autophagy and lipid metabolism. Many of these effects are mediated through the mTOR pathway. Conversely, the mTOR pathway influences the composition of the gut microbiota by controlling gut barrier function.
In addition, gut microbiota can regulate the mTORC signaling pathway, thereby inhibiting tyrosine phosphorylation, reducing protein levels, and downregulating insulin signaling, exerting the influence of gut microbiota on diabetes.
Nakamura et al. found that insulin-stimulated proximal tubular sodium transport is mediated by the Akt2/mTORC2 pathway, while insulin-inhibited proximal tubular gluconeogenesis is mediated by the IRS1/Akt2/mTORC1/2 pathway.
The interaction mechanism between mTOR pathways is shown in Figure 2.

 
Figure 2 Interaction mechanism between mTOR pathways and gut microbiota.

Through the aforementioned mechanisms by which gut microbiota affect type II diabetes, this literature also classifies and summarizes natural compounds that treat diabetes through gut microbiota. We will share with you in the next issue.

Literature source: Liying He, Fang-Qing Yang, Pan Tang, et al. Regulation of the intestinal flora: A potential mechanism of natural medicines in the treatment of type 2 diabetes mellitus [J]. Biomedicine & Pharmacotherapy, (151) 2022.

(The article is excerpted from popular science literature and does not provide any medical guidance.)