The Interrelationship Between Circulatory Metabolites,Gut Microbiome,and Clinical Outcomes In Coronary Heart Disease Patients Complicated With Nonalcoholic Fatty Liver Disease

PURPOSE:Coronary heart disease(CHD)is a global disease that seriously endangers human health.CHD is the "number one killer" threatening middle-aged and elderly population’s health.In population suffering from coronary atherosclerotic heart disease complicated with non-alcoholic fatty liver disease(CHD-NAFLD),the clinical prognosis is worse than those patients with CHD only.In recent years,it has been continuously reported that coronary atherosclerotic heart disease’s progression is associated with altered gut microbiota and metabolic profiles.However,it remains unclear how the gut microbiota and microbial-derived metabolites will affect CHD patients complicated with NAFLD,and whether this alteration in gut microbiome is associated with the poorer clinical prognosis of CHD-NAFLD patients.METHODS:We assessed the clinical prognosis of 27 CHD patients complicated with NAFLD,81 CHD patients without NAFLD.We also enrolled 24 matched healthy volunteers.Stool and serum were collected for intestinal flora 16S rRNA sequencing and serum metabolomics sequencing,respectively.Subsequently,prediction of gut flora function was achieved by using PICRUSt2 analysis.To find the nature and potential function of relevant metabolites,we look through database and literature review.Finally,Spearman correlation analysis revealed the association between alterations in the gut microbiome,serum metabolome and adverse cardiovascular events.RESULTS:Follow-up results showed that patients with CHD-NAFLD had a worse clinical prognosis and a significant higher percentage of cardiovascular accidents compared with patients with CHD only.Also,adverse cardiovascular outcomes were strongly correlated with serum metabolome shifts.By metabolomic analysis,we identified 25 metabolite modules.Serum metabolome changes in patients with CHDNAFLD exhibited increased cardiotoxic metabolites,such as prochloraz,aristolochic acid,and triethanolamine.While potentially beneficial metabolites,including estradiol,gibberellins,and palmitic acid,showed significant decrease.In addition,the profile of gut microbiome of CHD-NAFLD patients was altered,characterized by increased abundance of potentially pathogenic bacteria such as Oscillibacter ruminantium and Dialister invisus,while Fusicatenibacter saccharivorans.The increased abundance of potentially pathogenic bacteria in the CHD-NAFLD population was further confirmed by functional prediction analysis of PICRUSt2 flora.Furthermore,by Spearman correlation analysis,we found that changes in gut microbiota and serum metabolites were significantly associated with poor clinical prognosis in patients with CHDNAFLD,suggesting that abnormal gut microbiota in patients with CHD-NAFLD may produce harmful metabolites and release them into the circulation,which may lead to adverse cardiovascular events.CONCLUSION:Our findings suggest that in patients with CHD-NAFLD,the gut microbiome is significantly altered,which may lead to a worse clinical prognosis by altering the characteristics of metabolome in the blood circulation.We proposed the"liver-gut microbiota-heart axis" as a possible mechanism for this interrelationship.Our study provides new insights into the contribution of gut microbiota heterogeneity to CHD-NAFLD progression and suggests new strategies for disease treatment.