Association Of Intestinal Microbe And Metabolite Biomarkers With Clinical Symptoms In Patients With Schizophrenia At Different Stages Of The Disease

Objective:The brain-gut axis has gained increasing attention due to its contribution to the etiology of various central nervous system disorders.Several studies have found an association between neuropsychiatric disorders and alterations in gut microbial composition and their metabolites.Therefore,the aim of this study was to investigate the role of gut microbiota disorders and dysregulated gut metabolites in schizophrenia.Methods:A total of 124 participants were included in this study,41 in the acute and 39 in the remission group and 44 in the control group of schizophrenic patients.General information and feces were collected,and gut microorganisms and fecal metabolites were measured using a 16 S ribosomal RNA(16S r RNA)gene sequence method and a nontargeted liquid chromatography-mass spectrometry(LC-MS)based metabolic analysis method,respectively.All patients were assessed by the Positive And Negative Syndrome Scale(PANSS)and scores were recorded.Pearson correlation analysis was used to explore the relationship between differential gut microbes,differential gut metabolites and clinical symptoms.Results:(1)Demographic data,such as age,gender,BMI and educational level,were not statistically significant between the three groups(P>0.05),and there were no significant differences between patients in the acute and remission groups in terms of duration of illness and chlorpromazine equivalents(P>0.05).(2)Alpha diversity analysis showed no statistically significant difference between the three groups(P>0.05),Beta diversity analysis showed a statistically significant difference between the acute and healthy control groups(P< 0.05),while the results were not statistically different between the control and remission groups(P > 0.05)or between the acute and remission groups(P > 0.05).Moreover,this study found that 20 species of gut microbial composition were altered between the three groups,including three orders of bacteria,four families,nine genera and four species of bacteria.Among them,five intestinal microorganisms were significantly different between the acute and remission groups of schizophrenia,namely Dialister,Megasphaera,Bacteroides＿fragilis,Actinomycetaceae,and Clostridium.(3)The results of the untargeted metabolomic analysis of faeces suggested that a total of 145 differential gut microbial metabolites were detected between the acute,remission and healthy control groups of schizophrenia patients.The primary metabolic pathways involved in these metabolites were mainly environmental information processing,metabolism,organismal systems and human disease.In addition,the main secondary metabolic pathways enriched for the above differential metabolites were the nervous system,endocrine system,lipid metabolism and amino acid metabolism.A further double comparison of the different metabolites between the three groups showed scatter plot results suggesting that 10 metabolites were elevated and 16 metabolites were decreased in the acute group compared to the healthy control group,while 12 metabolites were elevated and 8 metabolites were decreased in the remission group.(4)Pearson correlation analysis indicated that dysregulated gut microbes and microbial metabolites may have some association with various psychiatric symptoms.The results of the microbial-clinical symptom correlation heat map suggested that the results of the acute group suggested the presence of nine gut microorganisms associated with clinical symptoms,including Methylophilales,Methylophilaceae,Dialister,Clostridium,Megasphaera,Bacteroides＿plebeius,Ruminococcus＿torques and Streptococcus＿sobrinus.Only three intestinal microorganisms in the remission group were negatively associated with clinical symptoms,namely Actinomycetaceae,Clostridium and Bacteroides＿fragilis.The results of the heat map of intestinal metaboliteclinical symptom correlations suggested that the acute group results suggested the presence of nine metabolites associated with clinical symptoms,including ubiquinol,pantothenic acid,Sphingosylphosphorylcholine,Phylloquinone oxide,vitamin D2,7-aminomethyl-7-deazoguanine,4-methyl-5-thiazoleethanol,Luteolin and Niacin.A total of 11 metabolites in the remission group were associated with psychiatric symptoms.Further Sankey diagrams showed that in the acute group of schizophrenia,7-aminomethyl-7-deazaguanine and vitamin D2 were associated with Streptococcus＿sobrinus(r=0.771,P=0.009;r=0.648,P=0.043);ubiquinol was associated with Ruminococcus＿torques(r=0.889,P<0.001);pantothenic acid was associated with Dialister(r=0.796,P= 0.006)and Bacteroides＿plebeius(r=0.903,P<0.001)respectively;also,Streptococcus＿sobrinus were a significant influence in relation to cognitive deficit symptoms(r=0.423,P=0.006),negative symptoms(r=0.398,P=0.010);Ruminococcus＿torques was negatively associated with positive symptoms(r=-0.326,P=0.037);Dialister was a strong influential factor associated with depressive symptoms(r=0.440,P=0.004).The results showed that the interaction of four dysregulated intestinal microorganisms(Dialister,Ruminococcus＿torques,Bacteroides＿plebeius,and Streptococcus＿sobrinus)and four dysregulated intestinal metabolites(pantothenic acid,vitamin D2,7-aminomethyl-7-deazoguanine and ubiquinol)in the acute group of schizophrenia may have an impact on the expression of clinical symptoms in schizophrenia.Conclusion: The potential interaction of dysregulated gut microbes and microbial metabolites in the acute group of schizophrenic patients may jointly influence the expression of clinical symptoms in schizophrenic patients,which tentatively suggests that dysregulated gut microbes and their metabolites may be involved in the pathogenesis of schizophrenia.