| Objective: To explore how gut microbiome promotes the occurrence and development of coronary heart disease(CHD)by studying the differences of gut microbiome and metabolites among patients with acute myocardial infarction(AMI),unstable angina pectoris(UA),stable angina pectoris(SA)and control group without coronary heart disease(CHD).In addition,the most important bacteria or metabolites with potential probiotic effects affecting coronary heart disease were searched in large clinical sample data,and their effects and mechanisms were verified by in vivo experiments in mice,so as to provide a new direction for the treatment of coronary heart disease with gut microbiome probiotics.Methods: We included 371 samples,including 215 patients with coronary heart disease,53 patients with myocardial infarction,106 patients with unstable angina pectoris,56 patients with stable angina pectoris,and 156 patients without coronary heart disease in the control group.Basic information and biochemical indexes of samples were collected,and metagenomics sequencing was performed on feces.In addition,50 patients with coronary heart disease were randomly selected from the total population,including 15 patients with stable angina pectoris,28 patients with unstable angina pectoris,7 patients with myocardial infarction,and 50 patients without coronary heart disease as the verification cohort.Fecal untargeted metabolite sequencing was performed on individuals in the validation cohort.Through the annotated KEGG database of gut microbiome and metabolites,the mechanism that gut microbiome may affect coronary heart disease was explored.The results of multi-omics gut microbiome sequencing were analyzed by abundance difference analysis,intestinal type cluster analysis,random decision forest screening of machine learning,and diagnostic model prediction analysis to find important markers for the occurrence and development of coronary heart disease.Subsequently,we used atheroid-prone mice to verify the practical role of important markers.Finally,the mechanism of important markers was found by targeting short-chain fatty acids in mouse feces,16 s r DNA sequencing and related basic experiments.Results:1)The composition of gut microbiome was different between coronary heart disease patients with different severity and controls.There were 18 species of bacteria with significant differences among the four groups,and these different bacteria could have a linear relationship with sample information and biochemical indicators.2)Cluster analysis of gut microbiome showed that the proportion of coronary heart disease in the population with Faecalibacterium prausnitzii as the dominant bacteria was significantly reduced.3)The diagnostic model constructed by machine learning found that compared with intestinal microbes and metabolites of gut microbiome,Faecalibacterium prausnitzii was the most important among all subtypes of coronary heart disease,and the diagnostic efficiency of an independent gut microbiome could reach more than 70%.4)Through the annotation of intestinal microbial genes and gut microbiome metabolites in KEGG database,it was found that gut microbiome may affect coronary heart disease by affecting amino acid metabolism and vitamin metabolism.5)After 12 weeks of continuous gavage intervention in Apo E-/-mice,it was found that Faecalibacterium prausnitzii had anti-atherosclerotic effects,which were not related to lipid and blood glucose metabolism,but played a role by reducing systemic inflammation and inflammatory response in aortic plaques.6)Intragastric administration of faecalibacterium prausnitzii in Apo E-/-mice for12 weeks showed an anti-atherosclerotic effect,which was not related to lipid and glucose metabolism,but to the reduction of systemic inflammation and inflammatory response in aortic plaques.7)After the intervention of faecalibacterium prausnitzii in mice,intestinal permeability is also changed,and the content of LPS into the blood is reduced,thereby reducing the inflammatory response.8)The main mechanism by which faecalibacterium prausnitzii alters intestinal permeability is by increasing ZO-1 protein in the mechanical barrier and MUC-2 protein in the mucosal barrier.9)Faecalibacterium prausnitzii can reduce the plasma LPS level,and then relatively inhibit the TLR4/My88/NF-k B pathway to reduce the inflammatory response in the plaque.Conclusions: 1)gut microbiome is closely related to the occurrence and development of coronary heart disease.2)Faecalibacterium prausnitzii has anti-atherosclerotic effect.Its mechanism is that it reduces the level of LPS in the intestine and increases the expression of ZO-1 protein and MUC-2 protein,thereby reducing the level of LPS in the plasma,inhibiting the TLR4/My88/NF-k B pathway,andultimately reducing the inflammatory response in the plaque.Thus,the anti-atherosclerotic effect is achieved.3)Faecalibacterium prausnitzii has anti-atherosclerosis effect,and its mechanism is to reduce the level of LPS in the intestine and increase the expression of ZO-1 protein and MUC-2 protein,thereby reducing the level of LPS in the plasma.The anti-atherosclerosis effect may be achieved by inhibiting TLR4/My88/NF-k B pathway andultimately reducing the inflammatory response in the plaque. |
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