Studies On Improving The Oxidative Stress And Barrier Function Of Microbiota-gut-brain Axis In Autism Mice Model

Background and ObjectivesAutism spectrum disorder(ASD)is a complex,pervasive neurobiological disorder,characterized by impaired social and communication skills,as well as stereotyped behaviors and restricted patterns of interests.So far,several etiology have been proposed,including genetic susceptibility,immunological alterations and environmental exposure.ASD patients are reported they are characterized by high levels of oxidative stress.Oxidative stress can induce or enhance mastcell activation.which led to the secretion of numerous vasoactive,nuerosensitising and proinflammatory molecules relevant to ASDs.These moleculars disrupt the gut-blood-brain barrier,permitting enterotoxic molecules to enter to the brain and trigger neuroinflammation.Thus,our research aims at summarizing the charateristics of gut microbiota in ASDs,to explore the oxidative stress in gut and microbiome and its effect on gut barrier.In addition,we also used Mn-SOD to explore its effect on modulating behavior and barrier abnormalities in ASD mice.MethodsFirstly,the MEDLINE,EMBASE,Web of Science and Scopus were systematically searched.Human studies that compared the composition of gut microbiota in ASD patients and HCs using culture-independent techniques were included.Independent data extraction and quality assessment of studies were conducted according to PRISMA statement and Newcastle-Ottawa Scale.Phylogenetic Investigation of Communities by Reconstruction of Unobserved States(PICRUSt)was used to infer biological functional changes of the shifted microbiota with the available data.Secondly,we used valproic acid to establish the ASD mice model.The difference of gut microbiota,oxidative stress and gut barrier between ASD and normal mice were compared.The capability of the superoxide produing between two groups were also detected.We also utilize in-situ perfusion experiment to explore the damage effect of superoxide on gut barrier,and the effect of SOD on reparing gut barrier.At last,to explore the treatment effect of daily Mn-SOD intake for four weeks in ASD mice,the composition and function of gut microbiome,the metabolomics profiling in cecum content,the oxidative stress in gut and the gut barrier were all analyzed.In addition,the Mn-SOD on serum inflammation factors and the oxidative stress and blood-brain barrier in brain were also compared to explore the effect on the autistic behavior.Results1、Sixteen studies with a total sample size of 381 ASD patients and 283 HCs were included in the systematic review.The overall changing of gut bacterial community in terms of β-diversity was consistently observed in ASD patients compared with HCs.Furthermore,Bifidobacterium,Blautia,Dialister,Prevotella,Veillonella and Turicibacter were consistently decreased,while Lactobacillus,Bacteroides,Desulfovibrio and Clostridium were increased in patients with ASD relative to HCs in certain studies.2、Compared with control mice,the a-diversity of ASD mice decreased andβ-diversity has changed.Meanwhile,the relative abundance of Bifidobacterium and Akkermansia all decreased.The PICRUSTs indicated the Mn-SOD relative abundance in ASD significantly decreased.In addition,the tight junctions in gut barrier of ASD mice were damaged significantly.The capability of produing superoxide in ASD mice significantly elevated.The in-situ perfusion experiment verified the damage effect of superoxide on gut barriar,furthermore,using Mn-SOD can reverse this damage effect.3、Daily intake of Mn-SOD for four weeks,can effectively improve the composition of gut microbiota and metabolites in ASD mice.Supplementation with Mn-SOD can reduce the ROS level in gut and correct gut barrier.At the end,stereotyped behavior,anxiety behavior and social behavior were all improved by Mn-SOD.ConclusionThis systematic review demonstrated significant alterations of gut microbiota in ASD patients compared with HCs,strengthened the evidence that dysbiosis of gut microbiota may correlate with behavioral abnormality in ASD patients.The gut microbiota and oxidative stress dysbiosis existed in ASD mice.The gut microbiome of ASD mice could produce superoxide,which further damage the gut barrier.Targeting the oxidative stress in microbiota-gut-brain axis,stable Mn-SOD could modulate behavior and barrier abnormalities in ASD mice.