Study On The Molecular Mechanism Of Stress-induced Hyperuricemia Based On Metabolomics As Well As Microbiome And The Effect Of Sini Decotion

Objective:Hyperuricemia(HUA)is a common public health problem at home and abroad,which can cause gout,cardiovascular disease,chronic kidney disease and other.The mechanism of hyperuricemia is complex,which can be divided into two aspects:the production and the excretion of uric acid,which are related to diet,living habits,genetics,etc.However,the mechanism is still not clear.Stress is produced when the external negative factors influence beyond the individual’s psychological and physiological ability to bear and produce negative effects,which can increase the risk of mental and physical diseases.Many studies have demonstrated that stress and stress hormones are closely related to uric acid production.Sini decoction is a famous prescription for anti-depression in traditional Chinese medicine.Sini Powder has been used in hyperlipidemia,diabetes and other metabolic diseases.The study of stress effects on hyperuricemia and the effect of Sini decoction can explore the mechanism of hyperuricemia and provide a new therapeutic idea.Methods:Model of acute hyperuricemia was successfully constructed by injection of inosine,and stress state was produced by water and restrain.The effects of hormones and receptors were investigated by stress hormones and receptor blockers.The mice were subjected to 14-day stress operation to produce a chronic stress model.Feces were collected for microbiome detection.Finally,injection of inosine was administered to each group.The changes of xanthine dehydrogenase(key enzyme of uric acid production)in related organs were detected to observe the effect of stress on uric acid production and the intervention of Sini decoction.Results:The uric acid in serum was significantly increased by water restrain,and epinephrine increased uric acid in a higher level.Propranolol antagonized the uric acid raising effect of water restrain and epinephrine,while phentolamine had no obvious effect on it.Stress in 14 days can significantly increase the uric acid in serum,as well as decreased the depression-like changes,and Sini decoction can resist the increase of uric acid as well as depression-like changes.In addition,there was no significant difference in xanthine dehydrogenase staining positive areas in liver among all groups,but water restrain could make the staining positive area of xanthine dehydrogenase in small intestine more obvious,and the phenomenon of staining positive aggregation was found in villi and chylous canals.The results of microbiome analysis in mouse feces suggest that stress can significantly change the composition and structure of intestinal flora,and affect the purine metabolism,amino acid metabolism and other functions of intestinal flora.The results of serum metabolomics suggest that stress can significantly change the purine-related and amino acid-related metabolites in serum,and there are many positive correlations between them,suggesting that stress may affect the purine metabolism of mice and lead to the increase of uric acid by regulating the amino acid metabolism of intestinal flora.Sini decoction can restore the serum purine and amino acid related metabolites.In addition,Sini decoction can significantly increase the contents of guanidine acetic acid and ornithine in serum,decrease the contents of glycine and arginine in serum,and reduce the supply of key amino acids in the process of purine synthesis.Conclusions:Stress and epinephrine can obviously promote the increase of uric acid.Stress can significantly increase the expression of xanthine dehydrogenase in small intestine,change the functions of purine metabolism and amino acid metabolism in intestinal flora,and change the levels of purine and amino acid-related metabolites in serum.Sini decoction regulates purine metabolism and amino acid metabolism of intestinal flora,improves creatine metabolism related materials such as guanidine acetic acid in serum,affects the supply of amino acid in the process of purine metabolism.These may play a important role in resisting the increase of uric acid caused by stress.