A Metabolite Perspective on the Involvement of the Gut Microbiota in Type 2 Diabetes

Abstract

Type 2 diabetes (T2D) is a commonly diagnosed condition that has been extensively studied. The composition and activity of gut microbes, as well as the metabolites they produce (such as short-chain fatty acids, lipopolysaccharides, trimethylamine N-oxide, and bile acids) can significantly impact diabetes development. Treatment options, including medication, can enhance the gut microbiome and its metabolites, and even reverse intestinal epithelial dysfunction. Both animal and human studies have demonstrated the role of microbiota metabolites in influencing diabetes, as well as their complex chemical interactions with signaling molecules. This article focuses on the importance of microbiota metabolites in type 2 diabetes and provides an overview of various pharmacological and dietary components that can serve as therapeutic tools for reducing the risk of developing diabetes. A deeper understanding of the link between gut microbial metabolites and T2D will enhance our knowledge of the disease and may offer new treatment approaches. Although many animal studies have investigated the palliative and attenuating effects of gut microbial metabolites on T2D, few have established a complete cure. Therefore, conducting more systematic studies in the future is necessary.

Keywords: bile acids; dietary diet; gut microbiota; metabolites; short-chain fatty acids.

Figure 1

Metabolites of the gut microbiota in dysbiosis and eubiosis. GPR: G protein-coupled receptor; GLP: glucagon-like peptide; PYY: peptide YY.

Figure 2

Effects of gut microbiota, microbial metabolites, and bacterial components on T2D. The host enzyme specifically converts the microbial metabolite TMA (Trimethylamine) to TMAO (Trimethylamine N-Oxide), and higher TMAO levels have been seen in people with IR. On the other hand, some bacterial metabolites such as SCFAs have been found to improve glucose homeostasis and IR by influencing epigenetic programming. This is due to their ability to inhibit the activity of the histone deacetylase enzyme. Furthermore, it is not just live bacteria that can affect health outcomes. Bacterial substances such as LPS (lipopolysaccharide), flagellin, and peptidoglycan have been identified as potential causes of an inflammatory reaction, thereby increasing the risk of developing T2D. In conclusion, the role of gut microbiota and its various components in health and disease is complex and requires further study to better understand its mechanisms and potential therapeutic implications.

Figure 3

The intestinal barrier is disturbed in people with obesity and diabetes. (1) A high-fiber diet can support the function of the intestinal barrier by enhancing the expression of tight junction proteins and immune cell function. Antigen-presenting cells like dendritic cells constantly monitor the intestinal environment, presenting antigens to T and B cells, which can lead to immune tolerance or inflammation based on cytokine and antibody expression. To promote intestinal health, consuming foods high in fiber can be beneficial. (2) Thinner mucus layers in the intestines of those who have metabolic syndrome make it possible for opportunistic microorganisms to invade the intestinal lining and cause infections. Additionally, levels of IgA-positive B cells and IgA secretion are lower, leading to microbial alterations and the outgrowth of opportunistic pathogens. A Westernized diet can also cause the intestinal lining’s tight junction proteins to express less frequently, which can cause bacteria and PAMPs to move about. In diabetics, hyperglycemia (high blood glucose levels) can also increase bacterial translocation by decreasing tight junction expression via GLUT2. PAMPs can cause inflammation in various tissues, including adipose tissue, where macrophages multiply and amass. Adipose tissue macrophages in particular are in charge of low-grade inflammation, which is marked by elevated levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory cytokines.

Figure 4

Probiotics’ impact on T2D is mediated at the molecular level. Probiotics help the gut produce healthy metabolites including SCFAs and certain BAs, which boost the release of GLP-1 and PYY and lessen IR and dysfunctional insulin secretion. Probiotics also lessen generalized inflammation by changing the bacteria in the stomach.

Figure 5

Molecular mechanisms linking gut microbiota and host health in both healthy and pathological situations. In healthy situations, colonocytes use butyrate as an energy substrate through beta-oxidation in the mitochondria. This process consumes oxygen and helps maintain an anaerobic condition in the lumen. Additionally, butyrate binds to peroxisome proliferator-activated receptor gamma (PPARγ), which represses inducible nitric oxide synthase (iNOS), leading to a decrease in nitric oxide (NO) and nitrate production. Glycolysis increases, oxygen consumption lowers, and PPARγ activity decreases in pathological conditions with low butyrate levels in the lumen. Consequently, iNOS expression increases, leading to more NO production and an increased availability of nitrates for specific pathogens. Furthermore, butyrate can stimulate regulatory T cells (Treg) to reduce inflammation. In healthy colonocytes, the nuclear transcription factor aryl hydrocarbon receptor (AhR) is extensively expressed and active. The function of the intestinal barrier can change as a result of decreased AhR activity or agonist deficit. SCFAs, particularly endocannabinoids (eCBs), and BAs all activate a number of important receptors that are expressed by enteroendocrine cells (L-cells). The activation of these receptors increases the secretion of important gut peptides like GLP-1, GLP-2, and PYY. Together, the interactions between these molecular players and gut bacteria help to prevent metabolic endotoxemia and hepatic steatosis, decrease intestinal permeability, and increase insulin secretion and sensitivity. They also help people eat less and have lower plasma lipid levels. There is a correlation between all of these effects and less inflammation. On the other hand, opposing effects have been seen under pathological circumstances.