| Background: Heart Failure(HF)is a complex group of clinical symptoms and is currently the most important cause of death from cardiovascular disease,with a five-year survival rate similar to that of malignant tumors,and has become an important public health problem threatening human life and health.The intestinal flora as a "microbial organ" has been widely studied after the "heart failure and intestinal hypothesis" was proposed.Existing studies have demonstrated that the composition of the intestinal flora in heart failure patients is significantly altered compared to the healthy state.The altered intestinal flora is involved in the heart failure process through bacterial translocation or regulation of various metabolic pathways including trimethylamine/trimethylamine oxide,short-chain fatty acids,and bile acids.Meanwhile,modulation of the gut microbiota through dietary interventions,probiotic supplementation,fecal transplantation and application of microbial enzyme inhibitors to treat the disease has emerged as a potential therapeutic approach.Bile acids are produced in the liver and metabolized by enzymes produced by the intestinal flora,which are essential for maintaining a healthy gut microbiota and balancing lipid and glucose metabolism.Secondary bile acids are produced by metabolic modifications of the intestinal flora and act as signaling molecules involved in the progression of heart failure disease.The farnesoid X receptor(FXR,NR1H4),the most well-studied bile acid-activated nuclear receptor,controls bile acid synthesis,binding and transport,and lipid metabolism.FXR has been shown to be significantly increased after heart failure,and FXR antagonists exhibit significant cardioprotective activities such as anti-inflammatory,inhibition of cardiomyocyte apoptosis and fibrosis..Therefore,it is very important to study the intrinsic scientific connection between FXR and heart failure to develop effective clinical drugs.The representative formula of Qixin-Yiqi has been widely used in the treatment of cardiovascular diseases and has good prospects for development.Therefore,this thesis proposes to take intestinal flora as the entry point,select Qishen Yiqi formula with good cardiovascular protective effect as the drug base,use the transplanted intestinal flora combined with heart failure model,and conduct a series of pharmacological mechanism investigation for the common targets related to heart failure,in order to provide new ideas and new insights for the treatment of heart failure.Purposes:(1)To observe the protective effect of the Astragalus formula on heart failure and the effect of intestinal flora of heart failure patients on heart failure mice.(2)Transplanting intestinal flora from heart failure patients into mice and combining them with a heart failure model to explore the mechanisms and scientific implications of the role of intestinal flora in regulating heart failure.(3)Exploring the interventional effect of Qishen Yiqi formula on heart failure based on FXR regulation of pathogenic Th17 cell differentiation induced by intestinal flora.Methods:(1)Patients with clinically confirmed heart failure and healthy participants were recruited,serum and faecal specimens were collected from those enrolled,and cardiac function and related biochemical parameters were measured.Processing of faecal specimens and transplantation of faecal bacteria to healthy mice.(2)After transplantation of patient flora,a mouse model of heart failure was combined and the mediating effects of intestinal flora and the therapeutic effects of Qishen Yiqi formula on heart failure were observed using small animal ultrasonography,pathological staining,real-time fluorescent quantitative PCR,flow cytometry,immunofluorescent staining and protein immunoblotting.(3)To verify whether the therapeutic effects of Qishen Yiqi formula are mediated through FXR-related pathways regulating cardiac inflammation and metabolic remodeling by overexpression and silencing of FXR,a key receptor for secondary metabolism of bile acids in the intestinal flora,using lentiviral transfection.(4)To explore the regulatory effect of FXR on pathogenic Th17 cell differentiation by immunofluorescence,flow cytometry and cell sorting,as well as the interventional effect of Qishen Yiqi formula.Results:(1)Administration of the Qishen Yiqi formula significantly improved cardiac function,attenuated the infiltration of pro-inflammatory-type cells in the heart,and corrected the energy metabolism disorder after heart failure in mice with heart failure.The intestinal flora of heart failure patients was able to accelerate the deterioration of cardiac function and metabolic disorders and promote the occurrence of adverse ventricular remodeling in heart failure mice.Serum-targeted metabolomics in mice showed that mice with heart failure have significantly different bile acid metabolic profiles.(2)FXR overexpression exacerbated the deterioration of cardiac function and myocardial injury after heart failure,but had no significant effect on reducing inflammation and improving cardiac energy metabolism,while FXR silencing showed good cardioprotective effects,improved cardiac function and myocardial injury in mice with heart failure,and ameliorated the inflammatory internal environment and energy metabolism disorders after heart failure.(3)It was verified that FXR has a regulatory effect on the differentiation of pathogenic Th17 cells,and Astragalus membranaceus can interfere with this process.Conclusion: Qishen Yiqi formula reduces pathogenic Th17 cell differentiation induced by intestinal flora through inhibition of FXR expression for the treatment of heart failure... |
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