Effects Of Rifaximin On Depression-like Behaviors Of Chronic Stressed Rats By Regulating Intestinal Intestinal Flora And Tryptophan Metabolism In The Hippocampus

1.BackgroundMajor depressive disorder(MDD)has been recognized as one of the leading causes of disability worldwide and a major risk factor for suicide.The clinical application of traditional antidepressants is limited due to slow onset,unsatisfactory efficacy,and poor tolerance of patients.Therefore,finding safer and more effective antidepressants has become an urgent problem.The intestinal flora is involved in the regulation of many important physiological processes.Recently,it has been found that the intestinal flora and the "gut-brain" axis are closely related to the pathogenesis of depression.Intestinal flora affects brain function through immunomodulatory,vagal,and neuroendocrine pathways.Among them,the neuroendocrine pathway affects the balance of central neurotransmitters and participates in the pathogenesis of depression by regulating the secretion of neurotransmitters,such as 5-hydroxytryptamine(5-HT).Tryptophan(TRP)is catabolized in the brain into kynurenine(KYN),serotonin and indole derivatives,and studies have suggested that peripheral or central kynurenine metabolites in patients with depression abnormal levels,changes in kynurenine metabolites were significantly correlated with depressive episodes and severity of symptoms,and the decrease in 5-HT was closely related to the onset of depression.Indoleamine2,3-Dioxygenase-1(IDO1)and tryptophan hydrogenase 2 Enzyme(TPH2)are key rate-limiting enzymes in the tryptophan metabolism pathway.It plays an important role in the metabolism of kynurenine and 5-hydroxytryptamine.Rifaximin is a broad-spectrum antibiotic that acts directly on the intestine and has little interaction with other kinds of drugs.In recent years,it has been reported that rifaximin can improve the disturbance of intestinal flora caused by stress and has a certain effect on the correction of tryptophan metabolism.Based on this,we hypothesize that rifaximin may play an antidepressant role by correcting intestinal flora imbalance and thereby affecting the tryptophan metabolic pathway.2.ObjectivesTo explore the antidepressant effect and mechanism of rifaximin on chronic unpredictable mild stress-induced depression model rats,and provide a theoretical basis for developing a new approach to treat depression.3.Materials and Methods(1)Forty-eight male Wistar rats(21 days old)were randomly divided into control group(CON),rifaximin administration group(R),CUMS model group(CUMS)and CUMS model+rifaximin administration group(CUMS+R).After one week of adaptive feeding,the CON group was treated with normal saline,the R group was treated with rifaximin for 4 weeks,the CUMS group was treated with chronic unpredictable mild stress for 4 weeks,and the CUMS+R group was treated with 4 weeks of chronic Unpredictable mild stress modeling and rifaximin treatment.(2)After modeling,used sugar water preference test,open field test,elevated plus maze test,and Morris water maze test to evaluate depression and anxiety-like behaviors in rats,including anhedonia,voluntary movement,depression-like behavior,anxiety-like behavior and Spatial memory ability.(3)16S rRNA sequencing was used to detect the composition of intestinal flora in rats.(4)Chromatography-mass spectrometry was used to detect the key molecules of tryptophan metabolic pathway in the hippocampus.(5)Quantitative Real-time PCR(qPCR)and Western blotting(WB)were used to detect the expressions of IDO 1 and TPH2 in rat hippocampus.4.Results(1)Chronic unpredictable mild stress leads to a reduction in the ratio of sucrose solution consumption in rats in the sugar-water preference test,and reduction in the number of cross-cells and central cell residence time in the open-field test,found in the Morris water maze test on days 3 and 4 of the training period The incubation period of the platform is extended,the number of crossing the platform during the test period is reduced,and the dwell time in the target quadrant is reduced.Results in obvious depression,anxiety-like behavior,and impairment of learning and memory in behavioral tests of rats.(2)Chronic unpredictable mild stress increases the expression of IDO1 in the hippocampus,decreases the expression level of TPH2 in the hippocampus,and induces the disorder of intestinal flora and tryptophan metabolic pathway in the hippocampus.(3)Rifaximin reverses depression and anxiety-like behaviors to a certain extent,normalizes intestinal flora and tryptophan metabolism,decreases the expression of IDO1 in the hippocampus,and increases the expression of TPH2 in the hippocampus.5.ConclusionsRifaximin ameliorates depression-like behavior in CUMS rats by affecting intestinal flora and tryptophan metabolism.