Shenqi Tangluo Pill demonstrates protective impacts on kidney damage in mice with type 2 diabetes through modulation of intestinal flora and the microbial metabolic product Trimethylamine N-oxide (TMAO).

内容摘要

Those affected by Type 2 diabetes (T2DM) often encounter microvascular harm, and within this context, the kidneys are especially prone to damage. Among the approaches to manage such microvascular complications, Shenqi Tangluo Pill (SQTLW), a traditional Chinese herbal formulation, is commonly utilized in clinical settings for preventing and addressing microvascular issues linked to T2DM. Nonetheless, the detailed impacts and working principles of this herbal formulation in alleviating kidney damage caused by diabetes are still not clearly understood. The aim was to confirm the kidney-protective impacts of SQTLW on T2DM mice, as well as to clarify the fundamental mechanisms related to intestinal microbiota and the microbe-derived metabolite trimethylamine N-oxide (TMAO), especially under the condition of intestinal flora depletion induced by a combination of broad-spectrum antibiotics (ABx). Diabetic db/db mice received sustained SQTLW intervention over an 8-week period. Following the 8-week intervention, evaluations were performed on fasting blood glucose levels (FBG), body mass, kidney function, and histopathological changes in renal tissue. Additionally, the makeup of gut microbial communities and the circulating concentrations of metabolites linked to TMAO were assessed. To assess the integrity of the intestinal barrier, histopathological examination of colonic tissue and expression profiles of zonula occludens protein-1 (ZO-1) and Occludin were performed. Expression levels of NOD-like receptor pyrin domain-containing 3 (NLRP3), Smad family member 2/3 (Smad2/3), fibronectin (FN), and α-smooth muscle actin (α-SMA) in renal tissue were examined using immunodetection methods. Next, db/db mice were given a combination of ABx and SQTLW treatments to further examine if the therapeutic outcome is dependent on the regulation of gut microorganisms. SQTLW notably lowered FBG and body weight in db/db mice, ameliorated renal dysfunction, and alleviated histopathological injury of renal tissue, with a notable dose-response relationship. 16S rRNA gene sequencing-based profiling revealed that SQTLW substantially altered the compositional structure of distinct bacterial genera from the phyla Bacteroidota and Firmicutes, particularly Muribaculaceae and Lachnospiraceae. Colonic histopathology and molecular detection indicated that SQTLW effectively preserved intestinal barrier architecture. Targeted metabolomics via LC-MS/MS demonstrated that SQTLW significantly modulated TMAO-related plasma metabolites, including TMAO, choline, and creatinine. Moreover, SQTLW significantly downregulated renal expression of NLRP3 and Smad2/3, thereby attenuating fibrosis-related injury. Importantly, further experiments confirmed that depletion of gut microbiota by ABx partially attenuated the renoprotective effects of SQTLW in db/db mice. SQTLW confers protective effects against renal injury secondary to T2DM, potentially via modulation of gut microbial composition, preservation of intestinal barrier function, and regulation of TMAO-related metabolic pathways.