| This study was part of "Research for the mechanism of Chicory granules treating hyperuricemia"(NO.20120013130002),which was supported by priorities of development of the Doctoral Scientific Fund(PFDR).The study is to investigate the clinical efficacy and security of Chicory granules,then to elucidate the urate lowering mechanism of Chicory granules base on the alteration of intestinal flora.Purposes and Significance of the ResearchAs the improvement of human living standards and the change in dietary structure,there is a rising trend in the prevalence of hyperuricemia around the world.Some information of the China expert consensus on hyperuricemia in 2013 was that the incidence rate of hyperuricemia was 5%-23.5%,which was close to western developed country.Hyperuricemia is not only an important biochemical basis of gout,but also is closely related to Metabolic syndrome(MS)and its components,such as hypertension,hyperlipidemia,diabetes,obesity,etc.and is closely related to cardiovas cular and kidney diseases,too.But the drugs for treatment of hyperuricemia is very deficient at present,which can not meet the clinical requirements.Hence,researching for new drugs for hyperuricemia is very necessary.Our research team had carried lots of studies on Chicory granules in the past two decades,we had investigated the raw material resources of Chicory granules,and had studied its composition,preparation technology,pharmacological effects and toxicology,etc.These experimental data have confirmed that Chicory granules has significant effect in decreasing blood uric acid,and the mechanism maybe related to inhibit uricogenesis enzyme activity.But its clinical efficacy and safety remains unclear.Therefore,in this study,we will conduct animal experiments and clinical trials to evaluate its clinical efficacy and safety,and the mechanisms as well.Studies have shown that the activity of uricogenesis enzymes,such as 5'-nucleotidase(5'-NT),purine nucleoside phosphorylase(PNP),Adenosine deaminase(ADA),Xanthione oxidase(XOD)would increase in many inflammatory diseases,producting lots of pro-inflammatory or Inflammation inhibition products,or rise to regulate purine metabolism to meet the energy demands for the inflammatory state.In recent years,studies have shown that gut bacteria and its metabolite,endotoxin(LPS),might induce systemic low-grade chronic inflammation.Would the inflammation mediated by LPS up-regulate the activity of XOD?ADA?5 '-NT?PNP?GDA?Does the Chicory granules reducing the content of serum uric acid be related to gut bacteria?Combined with clinical and the animal experiments,this topic will implement two research objectives.Firstly,to study the therapeutic effect of Chicory granules on hyperuricemia and its effect of invigorating speen to remove dampness.Secondly,based on the point of gut microbiota,to study the mechanisms of Chicory granules on hyperuricemia.Method(1)Clinical ResearchIn order to discover the curative effect of Chicory granules on hyperuricemia and to explore the impact of Chicory granules on the intestinal flora of hyperuricemia patients.Methods:Firstly,in virtue of clinical randomized controlled trial to interpretate the curative effect of Chicory granules.Secondly,with case-control study,investigated the differences of intestinal flora structure between normal volunteers and hyperuricemia patients,and the activity of XOD,ADA,5'-NT,PNP,GDA as well.Then,to discover the effect of Chicory granules on the microbiome composition in faeces of hyperuricemia patients,and LPS in plasma,Diamineoxidase(DAO),D-lactate(D-LA)content,and the activity of XOD?ADA?5'-NT?PNP?GDA in serum,etc.(2)Animal StudiesIn view of gut microbiota,we designed animal experiments to discover the pharmaco-mechanism of Chicory granules.Firstly,Hyperuricemia quail model was induced by high purine diet,then successive observed their serum uric acid,the activity of XOD,ADA,5'-NT,PNP,GDA,and the variations of microbiome composition,LPS content in plasma and in the cecum contents,pathological changes of cecum and ileum,to illustrate the pathological correlation of hyperuricemia and gut microbiota.Secondly,administrated antibiotics preventively to inhibit the quails' gut microbiota to prove the impact of gut microbiota and LPS on serum uric acid and the activity of XOD,ADA,5'-NT,PNP,GDA.Thirdly,to study the effect of Chicory granules on hyperuricemia quails and its pharmaco-mechanism based on the alteration of gut microbiota by observing their serum uric acid and the activity of XOD,ADA,5'-NT,PNP,GDA,the microbiome composition,intestinal barrier function,LPS content in plasma,pathological changes of cecum and ileum etc.Results(1)Pharmacology of Chicory granules on the treatment of hyperuricemiaClinical study showed that Chicory granules treated hyperuricemia patients for 1 month,who suffered from the spleen deficiency with too much dampness,the clinical efficacy rate reached 83.33%,the serum uric acid level decreased 23.41%.In addition,Chicory granules could assist to adjust blood-fat,protect liver,and could accommodate some syndrome,such as heaviness of limbs,poor appetite,loose stools,fatigue,etc.The Blood RT,Urine RT,and function of liver and kidney had no change.A small number of patients appeared mild abdominal distension or diarrhea at the beginning of treatment,and the symptoms mostly disappeared in a week.Few patients' symptom of abdominal distension was more severe and disappeared after themedicine was stopped.(2)Pharmaco-mechanism of Chicory granules on the treatment of hyperuricemiaThe clinical study showed that intestinal flora structure in feces of hypeluricemia patients was changed compared with normal control group,the content of lactobacillus and bifidobacteria which were the two main probiotics had discreased,the content of colibacillus and enterococcus faecalis had increased.The proportion of bifidobacteria and colibacillus declined.The content of LPS,DAO,D-LA in blood circulation increased,the serum uric acid and activity of XOD,ADA,5'-NT,PNP,GDA increased too.Chicory granules could increase content of bifidobacteria and lactobacillus in faeces,decreased content of colibacillus and enterococcus faecalis,decrease LPS content,DAO,D-LA in blood circulation and activity of XOD,ADA,5'-NT,PNP,GDA and serum uric acid.Animal studies showed that the hyperuricemia quails' intestinal flora structure changed,the change mainly related to bacteriodetes,firmicutes and proteo bacteria.Inflammation could be observed in cecum and ileum,and LPS may induce inflammation and up-regulate the activity of XOD,ADA,5'-NT,PNP,GDA,which lead to the production of uric acid increased.When administrated antibiotics preventively to inhibit the quails' gut microbiota,LPS in plasma decreased and activity of XOD,ADA,5'-NT,PNP,GDA decreased as well.Hence,it proved that LPS could up-regulate the activity of XOD,ADA,5'-NT,PNP,GDA.Chicory granules could regulate the intestinal flora,reduce LPS content in plasma,relieve inflammation and decrease the activity of XOD,ADA,5'-NT,PNP,GDA.Conclusion(1)In clinical research,it was confirmed preliminarily that Chircory granules can reduce serum uric acid of hyperuricemia,which provided favorable clinical evidence for development and clinical application of Chicory granules.(2)Combined with clinical studies and animal experiments,we discovered that gut bacteria and their pathological products LPS is one of the important reasons for hyperuricemia.(3)We discovered the impact of Chicory granules on the intestinal flora of hyperuricemia patients and explicited the mechanism of Chicory granules on treatment of hyperuricemia based on gut bacteria through animal experiments. |
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