The worldwide diabetic crisis is becoming more severe, affecting over 537 million adults, which is nearly 10% of the adult population globally. Most diabetics were not born with faulty blood sugar control. Nearly 95% have Type 2 diabetes (T2DM), a complex condition that develops gradually and has various underlying causes. In recent years, the gut microbiome has emerged as a participant in T2DM development and progression. This article will explore those connections as well as interventions targeting the microbiome to improve therapy.
Type 2 Diabetes, in brief
T2DM is characterized by pancreatic β-cell dysfunction and peripheral insulin resistance, leading to defects in glucose metabolism and chronic low-grade inflammation. Type 1 diabetes, on the other hand, is characterized by deficient insulin production and requires daily administration of insulin.
The development of this progressive metabolic disease (T2DM) is closely related to both genetic and environmental factors.
Immutable risk factors include family history, certain ethnicities, and older age. But significant predictors (yet alterable) include poor diet and inactivity along with excess weight. Indeed, the explosion of obesity as well as other environmental factors, such as air pollution, have resulted in soaring global rates of T2DM.
A healthy diet, regular physical activity, a normal body weight, and tobacco avoidance may prevent or delay the onset of T2DM. These lifestyle habits, medications, and regular screening are the foundation of treatment once a diagnosis is made.
Alas, diabetes is a major cause of blindness, kidney failure, heart attacks, stroke, and lower limb amputation. In 2019, diabetes and kidney disease due to diabetes caused an estimated two million deaths worldwide.
Arresting these deleterious macrovascular and microvascular outcomes calls for novel methods of prevention and treatment. The microbiome is one such area of investigation that researchers hope may one day offer clinical potential.
Microbial alterations in T2DM
Many studies confirm that gut microbiota is different in people with T2DM.
A 2020 systematic review of 42 studies in humans reported that the genera of Bifidobacterium, Bacteroides, Faecalibacterium, Akkermansia, and Roseburia were negatively associated with T2DM, while the genera of Ruminococcus, Fusobacterium, and Blautia were positively associated with T2DM.
In addition, substantial evidence of dysbiosis (imbalance in gut microbial populations) has been found in T2DM individuals, as reported in a 2022 review. For example, T2DM patients showed an increase in multiple pathogenic bacteria, while healthy controls had a high abundance of butyrate-producing bacteria such as Akkermansia muciniphila. Another study reported that patients with T2DM had a higher abundance of four Lactobacillus species and a lower abundance of five Clostridium species compared to normal glucose tolerance individuals.
A majority of patients with T2DM are overweight or obese, and obesity is considered the greatest risk factor for T2DM. Compared to healthy adults, obese and T2DM populations show changes in gut microbes and their metabolites, suggesting a role in the pathogenesis of T2DM.
Intriguingly, prediabetics (those with higher than normal blood glucose levels but not yet diabetic) also have aberrant gut microbiota, according to recent research.
Most clinical studies use stool samples, but the salivary microbiome has also been shown to be altered in T2DM. Tracking changes in the salivary microbiome may provide another useful means to monitor the development and progression of T2DM.
Mechanisms of microbial impact on T2DM
Because microbes are multitaskers in function, the mechanisms by which gut microbes influence glucose metabolism and insulin resistance are varied:
Crosstalk between the gut microbiota and host regulates local or systemic immunity and inflammation, which in turn contributes to the development of T2DM. Dysbiosis leads to increasing bacterial encroachment on the gut epithelium, triggering an inflammatory response. The intestinal barrier protects the body from intestinal contents, and its dysfunction increases the leakage of bacteria or bacterial products and thus leads to chronic inflammation and metabolic diseases.
Studies have confirmed that hyperglycemia increases intestinal barrier permeability by changing the integrity of tight and adherence junctions, resulting in a systemic influx of microbial products.
In addition, the gut microbiota is involved in the regulation of intestinal permeability. The mucus lining the gut epithelium is essential for the barrier function of the gut. Notably, bacteria-produced short-chain fatty acids (SCFAs) increase mucin production, which is important as mucin turnover is critical for intestinal barrier integrity. Loss of the mucin-degrading bacteria Akkermansia muciniphila is consistently noted in T2DM subjects. It has been shown that this bacterium reduced intestinal permeability by promoting the expression of tight junction proteins and improved glucose homeostasis in diabetic mice.
Butyrate and the other principal SCFAs acetate and propionate are important microbial metabolites produced via the fermentation of dietary fibers and other non-digestible carbohydrates.
Increasing evidence suggests that SCFAs may play an important role in the pathogenesis of T2DM. As noted, many studies have found that individuals with T2DM have a decreased amount of the species that produce the SCFA butyrate in their gut microbiome. Decreased abundance of butyrate producers has been linked to increased metabolic risks, whereas increased ingestion of dietary fibers has been specifically linked to the enrichment of butyrate-producing bacteria in human T2DM subjects and has also been shown to improve participants’ hemoglobin A1C levels (a blood test that shows average blood glucose level was over the past several months).
The mechanisms by which SCFAs affect T2DM include promoting insulin secretion, improving insulin sensitivity, activating intestinal gluconeogenesis, increasing energy expenditure, and reducing fat accumulation and inflammation.
Other microbial metabolites that are protective or causative for T2DM include some amino acids-derived metabolites and trimethylamine N-oxide.
Bile acids play key roles in regulating glucose homeostasis, and gut microbes are involved in modifying primary bile acids synthesized in the liver into secondary bile acids. The host and microbiome appear to regulate bile acid pool size through complex mechanisms. Changes in the composition and level of bile acids have been observed in patients with T2DM or insulin resistance.
Collectively, gut microbiota-related bile acids play an important role in the development of T2DM.
T2DM medications and the gut microbiome
The most commonly prescribed oral medication metformin may alleviate T2DM by affecting the microbiota and its microbial production of SCFAs. Some studies have shown that probiotics act as adjuvants to metformin by increasing butyrate production, thus allowing enhanced glucose management.
Microbiome-based interventions and T2DM
Prebiotics are substrates that are selectively utilized by host microorganisms conferring a health benefit. Often these are non-digestible carbohydrates. They have potentially positive effects on the management of T2DM by modulating gut microbiota and microbial metabolites.
Prebiotics such as inulin and the inulin-like fructan oligofructose (OFS) have shown promise for ameliorating T2DM phenotypes. Dietary supplementation with OFS has been associated with weight loss and improved glucose regulation in obese and overweight subjects. Similarly, fiber has consistently been shown to be beneficial in the management of T2DM.
In recent years, many studies have shown that probiotics have potentially beneficial effects on glucose homeostasis associated with T2DM.
A meta-analysis of clinical trials concluded that probiotic supplementation significantly reduced insulin resistance, fasting blood glucose, and HbA1c levels in T2DM patients.
Similarly, another meta-analysis concluded that probiotics might have a hypoglycemic effect in participants with T2DM, and this effect seems to be stronger in participants with poorly controlled diabetes and not receiving insulin therapy. For example, one trial reported that probiotic consumption (Lactobacillus acidophilus and Bifidobacterium animalis subsp. lactis) improved glycemic control in T2DM subjects.
In addition, next-generation probiotics such as Akkermansia muciniphila show potential for improving insulin resistance and glucose homeostasis in T2DM.
The possible mechanisms of action of probiotics include modulation of the gut microbiota, production of SCFAs and glucagon-like peptides, inhibition of α-glucosidase, raising SIRT1, reducing fetuin-A levels, and regulating the level of inflammatory cytokines.
Bariatric surgeries were originally intended to induce weight loss by limiting the amount of food the stomach can hold, thus reducing calorie intake. Roux-en-Y gastric bypass and sleeve gastrectomy, in particular, have also shown benefits for subjects with T2DM, including improved glucose metabolism, partly linked to post-surgical changes in the gut microbiome and resulting changes in SCFA levels.
Fecal microbiota transplantation
Fecal microbiota transplantation (FMT) refers to the transfer of fecal microbiota from a healthy donor to an unhealthy recipient via capsules with freeze-dried stool (or other ways); it may correct dysbiosis by increasing microbial diversity and restoring microbial function.
A recent study in T2DM mice showed that FMT could alleviate hyperglycemia, improve insulin resistance, inhibit chronic inflammation of pancreatic tissue, and attenuate pancreatic β-cell apoptosis.
In humans, a study on male recipients with metabolic syndrome reported beneficial effects of lean donor FMT on glucose metabolism that were linked with “changes in intestinal microbiota and plasma metabolites and can be predicted based on baseline fecal microbiota composition.” However, the adverse effects of FMT are worrisome because it may simultaneously transfer not only beneficial but also harmful microbes and their metabolites, which will affect FMT’s clinical application.
The gut microbiota and its metabolites are involved in the occurrence and progression of T2DM. Whether or not the disrupted microbiota is a contributor to or a consequence (or both) of the disease is not clear. Various interventions targeting the gut microbiota include the use of prebiotics and probiotics, as well as bariatric surgery and fecal microbiota transplantation. The research is promising. Further studies are needed to explore which specific microbes are responsible for diabetes physiopathology and the molecular mechanisms at work.
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