Gut Microbiota and Type 2 Diabetes

Abstract

Type 2 diabetes is an inflammatory metabolic disease characterized by insulin insufficiency/insufficient use of insulin in the body, the prevalence of which has been increasing (1,2). Environmental factors and genetic predisposition contribute to type 2 diabetes (3). Disruption of the gut microbiota is among the environmental factors contributing to type 2 diabetes (4,5). In this review, the relationship between gut microbiota and type 2 diabetes is summarized.

Gut microbiota includes microorganisms such as bacteria, archaea, fungi, and viruses that have settled in the gastrointestinal tract. Some functions of the gut microbiota, which has a symbiotic relationship with the human body, have various effects on human health. These functions are regulation of the immune system and inflammatory processes, ensuring intestinal integrity, regulation of neural signals, and increasing the levels of vitamins and intestinal metabolites (6).

Intestinal microbiota includes six bacterial phyla, mainly Firmicutes and Bacteroidetes. Factors such as genetics, mode of birth, breast milk intake, diet, lifestyle, and antibiotic use affect microbiota diversity (8). The intestinal barrier, which prevents the passage of toxins, intestinal bacteria, and bacterial metabolites into the circulation, is protected by intestinal permeability formed by the interconnection of intestinal epithelial cells (9). As a result of the disruption of the intestinal barrier, intestinal permeability increases which leads to translocation of intestinal bacteria into the circulation (6,10). Lipopolysaccharides (LPS) in the cell wall of Gram-negative bacteria increase intestinal permeability. Translocation of LPS into the circulation cause metabolic endotoxemia, leading to low-grade chronic inflammation. The resulting metabolic inflammation increases proinflammatory cytokines and impairs insulin metabolism. Intestinal microbiota is the main factor of the increase in intestinal permeability in type 2 diabetes (11). Therefore, healthy intestinal barrier functions may protect from metabolic diseases such as type 2 diabetes (12).

Gut microbiota metabolites can protect the host from various metabolic diseases. These metabolites include short chain fatty acids (SCFAs), branched chain amino acids (BCAAs), imidazole, and indole (13). SCFAs, bile acids, BCAAs, imidazole propionate, and LPS are effective in type 2 diabetes and the most important of these metabolites is SCFAs (6). SCFAs (butyrate, acetate, and propionate) are produced when indigestible carbohydrates are fermented by bacteria in the gut. Butyrate is produced by phylum Firmicutes, while acetate and propionate are produced by phylum Bacteroidetes. Butyrate contributes to the immune system by showing anti-inflammatory effect (8). It also prevents the translocation of LPS into the circulation and thus prevents the initiation of proinflammatory processes (15). Butyrate contributes to glucose homeostasis by activating intestinal gluconeogenesis (8,13). Acetate, another SCFA, not only acts as an energy source in peripheral tissues but also participates in cholesterol biosynthesis in the liver and plays a role in lipogenesis. It also contributes to increased secretion of anorexigenic hormones that suppress appetite (13). Propionate passes through colonocytes, is transported to the liver where it functions as acetate, and acts as a substrate for gluconeogenesis in the liver (14,16). In addition, the increase in intestinal propionate production is associated with an increase in pancreatic ß cell functions independent from GLP-1 increase (13).  Short-chain fatty acids also suppress glycolysis and gluconeogenesis by directly affecting hepatic glucose metabolism, increasing glycogen synthesis and decreasing plasma fatty acid concentrations. Short-chain fatty acids have also been shown to increase peripheral glucose uptake by increasing the formation of glucose transporter type 4 (GLUT4) (13). Because of the role of short-chain fatty acids, reduction in the bacteria producing these acids may lower these beneficial effects and promote the development of insulin resistance and type 2 diabetes (17). Intestinal bacteria play a role in the production of secondary bile acids, which regulates hepatic glucose metabolism and insulin sensitivity by stimulating GLP-1 secretion (18). Trimethylamine (TMA) is an organic compound synthesized from food, exclusively by the gut microbiota. Once absorbed, it is converted to trimethylamine N-oxide (TMAO) in the liver. Plasma TMAO levels are associated with increased risks of type 2 diabetes and cardiovascular disease (19).

Disturbances in the intestinal microbiota, caused by both internal and external factors, lead to a decrease in bacterial diversity that results in the formation of an unhealthy intestinal flora called dysbiosis. In intestinal dysbiosis, the formation of LPSs produced from the outer membrane of Gram-negative bacteria is triggered which warns the natural immune system and increases the release of proinflammatory cytokines that damage insulin signaling (20). Intestinal dysbiosis is directly associated with altered SCFA production (21). Butyrate and propionate administration increases GLP-1 and PYY levels and decreases insulin and leptin levels (23). Intestinal microbiota interacts with type 2 diabetes. Disrupted gut microbiota may be associated with type 2 diabetes, causing intestinal dysbiosis (12).

While the number of butyrate-producing bacteria decreases in type 2 diabetes, the number of pathogenic bacteria increases (6). In a study conducted in individuals with type 2 diabetes in China, there was a decrease especially in butyrate-producing bacteria among SCFAs (27). Zhang et al. (30) observed that while butyrate-producing bacteria were found intensively in healthy individuals, the amounts of Bacteroidetes and Verrucomicroniae were low in individuals with type 2 diabetes.

Probiotics are non-pathogenic live microorganisms with beneficial effects on intestinal and human health when taken in appropriate amounts (17). Probiotics are important for the management of type 2 diabetes by decreasing the Firmicutes/Bacteroidetes ratio and proinflammatory cytokines, increasing SCFA-producing bacteria and GLP-1 levels (12,37).  It also prevents the colonization of pathogenic microorganisms on the intestinal surface, reduces intestinal barrier permeability and LPS translocation, and increases beta cell mass (17).  Application of Lactobacillus reuteri in 31 glucose-tolerant individuals for 4 weeks showed that GLP-1 and insulin secretions were increased without any change in insulin sensitivity (40). Probiotic supplementation with Lactobacillus reuteri, for 12 weeks in individuals with type 2 diabetes receiving insulin treatment, improved insulin sensitivity but did not change HbA1c values indicating long-term glycemic control (41).

High-fat diets increase LPS levels in the gut microbiota and circulation, thus lead to metabolic endotoxemia (51). High-fat and low dietary fiber consumption increases body weight and insulin resistance (53).

Prebiotics, the nutrients of probiotics, consist of fermentable polysaccharides such as indigestible inulin, fructooligosaccharides (FOS), galactooligosaccharides (GOS), and lactulose. Prebiotics are fermented in the colon to produce SCFA. Positive contribution of prebiotic consumption to both appetite metabolism and glucose metabolism are mediated by SCFAs (38,39,54).

Inulin is the prebiotic that has the most evaluated association with type 2 diabetes.  Bifidobacterium and Bacteroidetes ratios and fecal FGCl concentrations were found to be higher in individuals with type 2 diabetes consuming inulin than those consuming placebo (55). There are studies showing that symbiotic use of prebiotics and probiotics provides more beneficial effects than their usage alone (57). In the presence of inulin with Lactobacillus acidophilus, butyrate production was 14.5 times higher when its used alone (58).

Gut dysbiosis may play an important role in type 2 diabetes by negatively affecting body weight, proinflammatory activity and insulin sensitivity. Although the mechanisms underlying these functions are still unclear, the gut microbiota should be considered as an important potential actor in treatment of metabolic disorders such as type 2 diabetes. Long-term and well-planned randomized controlled trials are needed before gut microbiota modulation can be considered as a therapeutic option to improve glycemic control and reduce the risk of complications of type 2 diabetes.