DISCUSSION
insulin and blood sugar, hyperlipidemia, Intestinal microbe dysbiosis, gastrointestinal tract, Parkinson’s disease, hypoglycemic, T2DM, metabolic traits, diabetes
IRRITABLE BOWEL SYNDROME, HYPERTENSION, HYPERLIPIDEMIA, CHRONIC DISEASES, METABOLIC DISEASES, INSULIN RESISTANCE, INSULIN RESISTANCE, INSULIN SENSITIVITY, DIABETES
Intestinal microbe dysbiosis is associated with the occurrence of various metabolic diseases such as T2DM, hypertension, and hyperlipidemia (Insulin resistance is a pathological condition in which cells become nonresponsive to insulin, and the pancreas is signaled to secrete even more insulin to reduce blood sugar. Eventually, the cells become even more insulin resistant, causing elevated levels of both insulin and blood sugar. Our results suggested that the coadministration of probiotics was able to significantly improve the functional index of insulin β-cells, but no significant differences were found for the insulin resistance and insulin sensitivity levels (Gutt index and quantitative insulin sensitivity check index [QUICKI]) between the two groups. The homeostasis model assessment-estimated insulin resistance (HOMA-IR) index is the most common clinical indicator of insulin resistance, but its response to dynamic insulin secretion is limited (Some previous studies found that the hypoglycemic effect of metformin is obvious through oral intake but not via intravenous injection, implying that the mechanism of action of metformin is directly related to the gastrointestinal tract (Several interesting observations were made. First, our data showed that the Simpson index was significantly higher in the probiotic group than in the placebo group after the intervention. In general, decreased microbiota diversity is considered an unhealthy state as it is indicative of a disrupted state of gut homeostasis, which frequently occurs due to external factors such as antibiotics and drug interference. Disturbances of the gut microbiota often affect the normal metabolism and immunity of the host. In clinical scenarios, reduced alpha diversity of gut microbes is commonly observed in various chronic diseases such as Parkinson’s disease and irritable bowel syndrome (To identify subtle but meaningful changes in the gut microbiome that are potentially related to symptom improvement, changes in responsive SGBs were analyzed. The second interesting observation was that the abundances of some beneficial SGBs, especially those related to SCFA production, were significantly increased in the probiotic group after the intervention, A previous study analyzed the fecal SCFA (including acetate, propionate, and butyrate) levels in 952 normoglycemic volunteers using two-way Mendelian randomization by combining genome-wide genotyping and intestinal metagenomic and metabolomic data, concluding that the increase in the gut production of SCFAs (especially butyrate) had great beneficial effects on the insulin response, energy balance, and metabolic homeostasis, but abnormalities in propionate metabolism could increase the risk of the development of diabetes, supporting that there is a causal effect of the gut microbiome on metabolic traits and the risk of T2DM (Third, metabolic pathway analysis found that the differential metabolites between the probiotic group and the placebo group were related mainly to the pathways of tryptophan metabolism, primary BA biosynthesis, and sphingolipid metabolism. Consistently, after the 3-month intervention, the fecal contents of some BAs, chenodeoxycholic acid and hyodeoxycholic acid, in the probiotic group were significantly higher than those in the placebo group. Chenodeoxycholic acid and hyodeoxycholic acid are related compounds, as chenodeoxycholic acid can be converted to hyocholic acid by the action of the CYP3A4 enzyme. It is known that BAs can act as signaling molecules to regulate the metabolism of glucose, lipids, and energy (Taken together, our results from metagenomics and metabolomics analyses supported that the coadministered probiotics acted synergistically with metformin to improve the clinical symptoms of T2DM patients possibly via two specific pathways (Schematic diagram showing the mechanism of clinical symptom improvement. Shown is a schematic representation of key pathways in the regulation of blood glucose metabolism and probiotic-driven host responses. SCFA, short-chain fatty acids; TGR5, G-protein-coupled bile acid receptor 1; FXR, farnesoid X receptor; ASBT, apical sodium-bile acid transporter; PYY, peptide YY; GLP-1, glucagon-like peptide 1.