Relationships of intestinal microbiota metabolites with biomarkers of oxidative stress in type 2 diabetes mellitus. Review

The review is devoted to the analysis of modern data on the relationships between pathogenetic mechanisms in dysmetabolic conditions (metabolic syndrome, type 2 diabetes mellitus) and the functional activity of the intestinal microbiota, which produces low‑molecular compounds classified by biological effects into two types: 1) beneficial for maintaining metabolic homeostasis and antioxidant system in the body, such as short‑chain fatty acids (SCFAs), bile acids and 2) so‑called «dangerous» metabolites, including endotheliotoxic trimethylamine‑N‑oxide (TMAO) and endotoxemia factors lipopolysaccharides (LPS). The molecular mechanisms that mediate SCFAs effects as mediators of oxidative eustress and cytoprotection in various pathologies have been considered. In addition to the role of energy substrates, SCFAs play the role of ligands of G protein‑coupled membrane fatty acid receptors, the activation of which triggers nuclear erythroid 2‑related factor 2 (NRF2) signaling pathways. This transcription factor plays a crucial role in the response to cellular stress, suppressing the expression of inflammatory cytokine and chemokine genes and contributing to the maintenance of redox homeostasis under physiological conditions. The second type of microbial metabolites, on the contrary, corresponds to the definition of oxidative distress factors that exhibit cytotoxic properties, contributing to the processes of atherogenesis and chronic inflammation, especially under the conditions of a dysbiotic state. For example, it has been shown that TMAO can affect mitochondrial and lysosomal signaling pathways, thereby increasing the concentration of reactive oxygen species and malondialdehyde. In addition, TMAO modulates the expression of microRNAs, which promotes the expression of pro‑inflammatory interleukins and blood coagulation factors. Other toxic metabolites, LPS, have a high pro‑inflammatory potential, they increase the permeability of the intestinal mucosa and provoke inflammation and oxidative stress in various tissues of the body. Thus, there is a significant progress in the study of the molecular mechanisms of positive and negative effects of microbial metabolites, which argues for the importance of correcting the composition of the intestinal microbiota and monitoring its functional activity in the process of complex treatment of diabetes mellitus and prevention of the development of cardiometabolic complications associated with oxidative stress.