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0THE IMPORTANCE OF THE STATE OF THE INTESTINAL MICROBIOTA IN DIABETES MELLITUS
12Khalmatova K.I., 3'4Shamansurova Z.M., 5Sanaeva P.Sh.
1Tashkent Pediatric Medical Institute, Tashkent 2Family clinic № 5, Tashkent 3Central Asian University School of Medicine, Uzbekistan, Tashkent 4 Institute of Biophysics and Biochemistry at National University of Uzbekistan, Tashkent
5 Tashkent City Teenage Dispensary https://doi. org/10.5281/zenodo. 13884743
Abstract. Today, according to statistics from the World Health Organization, approximately 422 million people, representing 6.028% of the total world population, suffer from diabetes [1]. This disease is characterized by chronic hyperglycemia caused by insulin resistance or deficiency. The largest number of cases among the various forms of diabetes is type 2 diabetes. Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia due to insulin resistance or insulin deficiency. This condition can lead to the development of microvascular (retinopathy, neuropathy, nephropathy) and macrovascular complications (coronary artery disease, peripheral arterial disease, stroke), which in turn increases the risk of morbidity and mortality [2].
Keywords: diabetes mellitus, gut microbiota, antihyperglycemic drugs, intestinal microflora.
Gut microbiota and its functions
Gut microflora performs a number of critical functions in the body, including processing, digesting and expelling pathogens, and synthesizing vitamins. In this regard, there is an assumption that the intestinal microflora acts as an endocrine organ, which is confirmed by its ability to produce and regulate various compounds that affect the function of distal organs and systems, including the brain [3]. Imbalances in the composition and function of the gut microbiota are associated with various gastrointestinal diseases such as inflammatory bowel disease, irritable bowel syndrome, as well as broader systemic manifestations such as obesity, type 2 diabetes and atopy. [4]. Treatment of DM using dietary changes, prebiotic/probiotic supplementation, and fecal microbial transplantation may correlate with targeted changes in dysbiosis. The effects of various antihyperglycemic drugs, such as metformin, and the effects of post-bariatric surgery on the diversity of intestinal microflora are also being studied. These research directions are important for understanding the pathogenesis of diabetes mellitus at the microbial level of metabolic and inflammatory mechanisms, which may lead to the development of new treatment strategies aimed at influencing the composition of the intestinal microflora and thereby mitigating inflammatory processes. The mechanisms of changes in the intestinal microflora have been studied in detail in patients with diabetes, which are associated with impaired insulin sensitivity and poor glycemic control [5].
The BM of patients with diabetes is dominated by pathogenic and opportunistic gramnegative bacterial species, such as Enterobacteriaceae, various Clostridiales, Escherichiacoli, Bacteroidescaccae and Lactobacilli, as well as Prevotellacopri and Bacteroides vulgates. Bacteroides are gram-negative microorganisms, the presence of which correlates with an increase
in lipopolysaccharides (LPS) and, on the contrary, their decrease is associated with a decrease in metabolic endotoxemia and inflammatory status. This in turn leads to the production of pro-inflammatory mediators such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor-a (TNF-a) and contributes to the development of insulin resistance and T2DM [6].
Changes in the dysbiotic profile are characterized by more species-specific than genus-specific changes. Some Clostridium species play a key role in the metabolism of hepatic bile acids (BAs) and their synthesis from cholesterol. FAs play an important role in glucose metabolism and energy homeostasis, and also have antimicrobial properties and are ligands for the farzenoid receptor (FXR), a receptor involved in the regulation of FAs, carbohydrate metabolism, insulin response and intestinal immune response. Activation of FXR in the ileum leads to a negative feedback mechanism, resulting in decreased denovo hepatic FA synthesis, gluconeogenesis, and activation of hepatic glycogenesis, which increases energy expenditure in muscle and adipose tissue and stimulates insulin production by pancreatic beta cells.
Consequently, dysbiosis and impaired FA synthesis can lead to chronic inflammation, increased insulin resistance and poor glycemic control [7].
Diet and Intestinal Microflora
The mainstay of diabetes treatment is lifestyle changes, including proper nutrition and physical activity. If non-drug treatment is followed along with medications, the therapeutic effect is enhanced. Research by Arumugam M et al. postulated that there are three different enterotypes of microbiota, characterized by different species composition and, in particular, the predominance of Bacteroides, Prevotella and Ruminococcus, respectively. Each enterotype is associated with a distinct dietary pattern: the first is associated with a Western diet, a diet high in saturated fat, which correlates with a higher inflammatory profile, blood LPS levels and endotoxemia, as well as reduced microbiota diversity, the same features found in humans with overweight and obesity. In contrast, a Mediterranean-type diet low in saturated fatty acids and refined sugars and high in fiber and unsaturated fatty acids, which belongs to the second enterotype, positively modulates the intestinal microbiota, providing protection against metabolic syndrome and diabetes, cardiovascular diseases and cancer. Dietary fiber reduces intestinal permeability and therefore the proinflammatory state associated with endotoxemia. Since fiber intake is associated with increased butyrate production, this mechanism may likely explain the preventive effect of a fiber-rich Mediterranean diet. Finally, the third type is the least common in the population, does not have a constant composition and is not associated with a specific diet [8]. The multitude of associations with various clinical conditions does not make the classification of enterotypes sufficiently specific as a separate diagnostic criterion for any disease, the varying effectiveness achieved with a particular dietary intervention in different enterotypes. It confirms the hypothesis that everyone should be offered an individual treatment strategy, in accordance with the composition of their microbiota.
Physical activity can also influence the composition of CM. High-intensity training negatively affects the digestive system, causing dysbiosis. Conversely, moderate-intensity exercise does not affect BM diversity but has a beneficial effect on its composition, increasing the relative abundance of Akkermansiamuciniphila and Oscillospira with increasing short-chain fatty acid content and lactic acid production [9].
Thus, taking into account the individual characteristics of the composition of CM in each patient, a personalized approach to treatment is proposed, taking into account diet, physical activity and medication.
Gut microbiota and TSSP
Gut microflora plays an important role in the effectiveness and safety of antidiabetic drugs. There is a number of data indicating that antidiabetic drugs can affect not only the composition of UA, but also the individual response of the body to drug exposure. The interaction between MK and antidiabetic drugs is complex and two-way. On the one hand, antidiabetic drugs such as metformin, GLP-1 receptor agonists, DPP4 inhibitors and SGLT2 inhibitors can affect the composition of UA. On the other hand, MK can affect the biological activity, bioavailability and toxicity of drugs [10].
Metformin is one of the most studied among tableted hypoglycemic drugs. Research suggests that some of its therapeutic effects may be mediated through effects on UA, as evidenced by a decrease in hypoglycemic effect when administered intravenously. MK metagenome analysis showed that metformin has an effect on the production of short-chain fatty acids (SCFAs) [11]. Increased production of SCFAs, especially butyrate and propionate, promotes the activation of intestinal gluconeogenesis, which improves glycemic control and reduces hepatic glucose production, as well as appetite and body weight. Metformin has been shown to induce a decrease in Clostridium bartlettii abundance, which correlates with less insulin resistance. In treatment-naive patients with type 2 diabetes, treatment with metformin results in an enrichment of Parabacteroides distasonis. Metformin also helps strengthen intercellular tight junction. Interestingly, the composition of UA during treatment with metformin becomes more similar to UA in healthy patients. There are also microbial groups that may predict the effectiveness of metformin. For example, increased presence of Prevotellacopri before treatment may limit the reduction in glycated hemoglobin (HbAlc) levels.
Moreover, metformin itself can change the composition of uric acid, leading to an increase in the abundance of Enterobacteriales and Akkermansiamuciniphila. The results of randomized controlled trials showed that when treated with metformin, there is an increase in the abundance of Escherichiacoli and Ruminococcus, and a decrease in the relative abundance of Intestinibacter bartlettii and Roseburia intestinlis [12].
If the therapeutic effects of metformin on glucose metabolism are mediated by CM, then some of its side effects may be caused by changes in CM. For example, the presence of metformin-induced Escherichia excess can lead to abdominal discomfort. On the other hand, modulation of BM composition by probiotics directly affects the transcriptional effect of FXR in the gut-liver axis [13].
Several studies in mice have shown that CM regulates glucose homeostasis and satiety via GLP-1 incretin secreted by intestinal L cells. GLP-1 receptor agonists are capable of causing changes in the ratio of Firmicutes and Bacteroides, modifying the composition of BM. In a mouse study, liraglutide administration promoted the expression of short-chain fatty acid (SCFA)-producing bacteria such as Bacteroides, Lachnospiraceae and Bifidobacterium. In addition, the administration of liraglutide leads to a decrease in Proteobacteria and an increase in Akkermansia muciniphila [14].
Thiozolindiones, as well as DPP-4 inhibitors such as sitagliptin and vildagliptin, have also shown the ability to modulate CM. DPP-4 inhibitors reduce blood glucose levels by blocking the
degradation of GLP-1 and restore the composition of BM, increasing the number of bacteroids. In rats, administration of sitagliptin increased the expression of Firmicutes and Tenericutes, while treatment with vildagliptin decreased the ratio of Firmicutes to Bacteroidetes and increased the number of Lactobacillisp and production of propionates [15,16].
SGLT-2 inhibitors reduce blood glucose by increasing urinary glucose excretion. Several studies have found that SGLT2 inhibitors have little or no effect on CM. On the other hand, in diabetic mice, treatment with dapagliflozin showed a reduced ratio of Firmicutes to Bacteroides and Oscillospira and an increase in the abundance of Akkermansiamuciniphila [17].
Conclusion
Diabetes mellitus and other metabolic diseases lead to quantitative and qualitative changes in BM. These changes in the microbiota may contribute to the development of inflammatory processes, hyperinsulinemia, insulin resistance and fatty liver steatosis. CM stands out as a new potential prognostic biomarker for diabetes and its complications.
Therefore, UA testing may represent a valuable tool for restoring eubiosis in people with dysmetabolism and as an adjuvant approach to improve response to pharmacological treatment and patient adherence to treatment by reducing the need for medication.
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