The “sweet” issue for public health
According to the International Diabetes Federation Diabetes Atlas (9th edition), approximately 463 million adults globally suffer from diabetes. This number is projected to rise to 578 million (10.2% of the total population) by 2030, making diabetes one of the most serious threats to human health in the 21st century. The global prevalence of T2DM is increasing, with factors like socio-economic changes, environment, and genetics contributing. The detrimental effects of diabetes have long been recognized. The main clinical symptoms of diabetes are increased food and water intake, increased urination, and body weight loss. Diabetes can cause complications in multiple organs, such as the cardiovascular system, eyes, kidneys, and nerves, severely reducing the quality of life of patients.
These complications have significant impacts on health—for example, significantly increased risk of heart disease and stroke. Recent studies showed that the incidence and mortality of cardiovascular and cerebrovascular diseases in patients with diabetes were about 3.5-fold higher than those in non-diabetic patients. Diabetes patients are prone to hypertension, coronary heart disease, and myocardial infarction. Diabetes can also cause serious damage to the glomeruli, leading to proteinuria, hypertension, a gradual decline in renal function, and potentially renal failure. Moreover, diabetes can cause neuritis and peripheral neuropathy, resulting in foot ulcers and necrosis and sometimes necessitating amputation in severe cases. In addition, diabetes can cause retinopathy, accompanied by the risk of blindness.
Recent research has highlighted the multifactorial nature of T2DM, expanding our understanding from early models to the more comprehensive “egregious eleven” pathways, with the gut microbiome now recognized as a critical factor. The understanding of T2DM’s pathophysiology has expanded from early models to include eleven pathways, with the gut microbiome now recognized as a key factor. Advances in sequencing technologies have shown the gut microbiome’s influence on metabolism and T2DM development. Industrialization, medication use, and western lifestyles have reduced gut microbial diversity, possibly leading to increased T2DM rates. This reduction in diversity, characterized by the loss of key bacterial species, may contribute to chronic inflammation and T2DM, though proving causality remains challenging.
Disruption of gut homeostasis in diabetes
Recent epidemiological, physiological, and omics findings, along with cell-based and animal experimental results, indicate that a significant portion of the environmental impact on human health and disease risk may be mediated or modified by the microbial community. In patients with T2DM, gut microbiota composition often shifts towards increased facultative anaerobic bacteria, reduced diversity, and fewer beneficial obligate anaerobes, a state known as dysbiosis. This dysbiosis is not uniform across all patients but varies significantly due to factors such as diet, medication, and immune health, which may contribute to disease progression in different ways. Some bacterial genera are negatively correlated with type 2 diabetes. In the gut microbiota of T2DM patients, the abundance of Bacteroidetes, Bifidobacterium, Akkermansia, Faecalibacterium and Roseburia was reduced.
In contrast, the abundance of Fusobacterium, Ruminococcus and Blautia in the gut microbiota of T2DM patients is higher than that in healthy controls. Of note, T2DM can also lead to significant decreases in the abundance of Bacteroides in the intestine. Patients with T2DM have a reduced abundance of Enterobacteriaceae, Bacteroides 20_3 and Bacteroides vulgaris. Roseburia, Faecalibacterium, lactobacilli, Ruminococcus and Blautia belong to the phylum Firmicutes and are negatively affected by diabetes. Patients with T2DM generally have reduced levels of Roseburia as compared with their healthy cohorts. R. intestinalis is positively associated with diabetes, while R. inulinivorans and Roseburia_272 are negatively associated with diabetes. Other studies have observed a decreased abundance of Faecalibacterium and F. prausnitzii in T2DM patients.
Much evidence has shown that gut microbiota influences the capacity of the distal intestine to secret hormones regulating blood glucose. Patients who have undergone complete colectomy have an increased risk of T2DM compared to those who do not have the surgery. Maintaining gut homeostasis— characterized by a healthy microbial community, strong intestinal barrier, and appropriate immune responses— is crucial for preventing metabolic diseases. Gut microbes produce key metabolites like short-chain fatty acids (SCFAs) and bile acids that are vital for host health, and disruption in their production is linked to diabetes. Therefore, addressing dysbiosis and promoting gut homeostasis involves more than altering the microbial composition; it requires a holistic approach that considers the patient’s diet, lifestyle and immune status.
T2DM is also linked to disrupted daily oscillations in gut microbiota, which may contribute to metabolic disorders. However, the reliance on fecal samples in most studies presents limitations, as these samples may not fully capture the microbial diversity across different regions of the gastrointestinal tract. Comprehensive gut sampling, across different intestinal regions, is essential to better understand these dynamics in T2DM. Chronic low-grade inflammation due to microbiota alterations further impacts host metabolism and promotes the growth of pathogens. Microbial metabolites produced in the gut significantly influence systemic physiology, particularly through interactions with the liver, highlighting the need for comprehensive gut sampling to better understand these dynamics in T2DM.
The gut microbiota as a causal mediator in the “egregious eleven”
In the β cell-centric model, hyperglycemia is viewed as the final stage of diabetes, explaining the various organ and system dysfunctions in diabetes, including insulin resistance (IR) and systemic inflammation. Gut microbiota plays a crucial role in these processes, influencing β cell function, metabolism, and inflammation through the production of key microbial metabolites such as SCFAs and branched-chain amino acids (BCAAs). Elevated BCAAs are linked to IR and T2DM, while bile acids and other microbial products affect glucose and lipid metabolism. Inflammation, driven by lipopolysaccharide from gut bacteria, exacerbates IR and β cell dysfunction. These interactions highlight the gut microbiota’s integral role in the complex network of factors contributing to diabetes, making it a key target for therapeutic interventions. Tryptophan metabolism by gut bacteria also influences diabetes, affecting glucagon-like peptide-1 secretion, β cell health, and systemic inflammation. Dietary management, particularly high-fiber diets, can modulate gut microbiota, potentially improving metabolic outcomes in diabetes by reducing inflammation and enhancing microbial diversity.
Interaction between oral antidiabetic drugs and gut microbiota
Gut microbiota not only responds to antidiabetic medications but can also predict drug efficacy and adverse effects. For example, metformin alters the gut microbial composition, enriching beneficial SCFAs while also contributing to side effects. This dual effect of metformin is mediated through its influence on specific microbial populations, such as the enrichment of beneficial bacteria like Akkermansia muciniphila, which may help improve glucose tolerance, alongside an increase in potentially harmful Escherichia species that could contribute to gastrointestinal discomfort. Antidiabetic medications may positively change the gut microbiota with an improvement in overall metabolic health. Several classes of antidiabetic medications have been studied in this regard, including metformin, thiazolidinediones (such as pioglitazone), and incretin-based therapies (such as GLP-1 receptor agonists and DPP-4 inhibitors). These medications may directly interact with gut bacteria or their metabolic pathways. For example, metformin has been shown to accumulate in the intestine, where it can directly affect the growth and metabolism of certain bacterial species. Therefore, the researchers suggest that gut microbiota should be considered in developing personalized antidiabetic treatments that optimize drug response and minimize side effects.
Therapeutic targeting of gut microbiota diversity
Given the role of gut microbiota in T2DM, therapies like prebiotics, probiotics, synbiotics, and fecal transplantation show promise. These approaches are not without challenges, as the effectiveness of these therapies can vary widely depending on individual microbiota compositions and the specific strains used. These approaches modulate gut bacteria to improve glucose control, insulin sensitivity, and metabolic profiles, offering potential adjunctive treatments to enhance efficacy and reduce side effects in diabetes management. In recent years, probiotics have been used to beneficially modulate the abundance of intestinal microbiota. Commonly reported probiotics include lactic acid bacteria (e.g., lactobacilli (formerly Lactobacillus), Bifidobacterium, Streptococcus), non-lactic acid-producing bacteria (e.g., Bacillus, Propionibacterium), non-pathogenic yeasts (e.g. Saccharomyces cerevisiae), and non-spore-forming and non-flagellated cocci. Among them, Lactobacillus and Bifidobacterium have been the most extensively studied. Lactobacilli includes different species, among which the probiotics are L. acidophilus, L. rhamnosus, L. delbrueckii subsp. bulgaricus, Lmb. reuteri, Lbs. casei, Lab. johnsonii and Lpb. plantarum. Bifidobacterium belongs to Actinobacteria, with common probiotic species including B. animalis, B. bifidum, B. breve, B. infantis, B. lactis and B. longum. Yogurts, kefir and other probiotic beverages are enriched with these strains.
Conclusion
In conclusion, the gut microbiota plays a crucial role in the pathogenesis of T2DM, offering potential for personalized treatment strategies. Despite the challenges in understanding microbial variability and establishing causality, ongoing research, and trials continue to refine our understanding and approach to microbiota-targeted therapies. They could also be a complement with a proper dietary style. Indeed, poor dietary structure and eating habits play significant roles in the onset and progression of T2DM, and an unbalanced diet is closely associated with gut microbiota dysbiosis. This dietary structure is characterized by chronic excessive consumption of carbohydrates and fats (particularly saturated fats) and inadequate intake of dietary fiber. Consequently, dietary interventions for patients with T2DM should focus on the overall dietary pattern rather than isolated nutrients or specific foods. This is because different dietary combinations and the nutrients contained within them interact synergistically to influence the health of individuals with T2DM. In the future, continued focus on identifying microbial signatures and refining interventions will be essential in advancing personalized medicine for diabetes.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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