| Atherosclerotic cardiovascular disease(ASCVD)remains the most common cause of death worldwide,and atherosclerosis(AS)is the common pathological basis for the disease.Therefore,delaying or inhibiting the occurrence and development of AS is an important measure to prevent and treat ASCVD.More and more studies have indicated that gut microbiota(GM)and metabolites involved in the occurrence and exacerbation of AS,and targeted regulation of GM and metabolites may become a potential therapeutic strategy for the prevention and treatment of AS.According to the preliminary study of our research group,the herb pair of Ginseng-Polygonum cuspidatum has a significantly anti-atherosclerotic effect,which based on the core pathogenesis of‘deficiency,blood stasis and toxin’ of AS.Study has demonstrated that this herb pair could improve the vascular elasticity of AS model mice,increase the content of smooth muscle and collagen in the plaques to reduce the vulnerability of plaques.The oral bioavailability of multiple compounds in this herb pair were found low by liquid chromatography-mass spectrometry.So,is the anti-atherosclerotic effect of Ginseng-Polygonum cuspidatum herb pair related to gut microbiota?Therefore,the present study explored the anti-atherosclerosis mechanism of Ginseng-polygonum cuspidatum from the perspective of intestinal microecology.This study includes four parts:Part 1 Characteristics of gut microbiota in patients with atherosclerotic cardiovascular diseaseObjective:To systematically analyse the characteristics of the gut microbiota of ASCVD population,and provide evidence-based basis for the prevention and treatment of ASCVD from the perspective of gut microbiota.Methods:We searched databases including PubMed,Embase,Scopus,and Cochrane Library.The main keywords included in the search were "Coronary artery disease","Ischemic heart disease","Coronary arteriosclerosis","Stroke","Peripheral arterial disease","Gastrointestinal microbiome","Gut microbiome","Gut microbiota",and so on.Subsequently,the references in the retrieved literature were checked to avoid omissions,and the language was limited to English.Two researchers independently extracted relevant data and evaluated the quality of included study.A semi-quantitative analysis was performed to summarize the specific gut flora associated with ASCVD.Results:(1)A total of 53 English literatures were included.The quality of 26 literatures was rated as "Good",26 as "Fair",and 1 as "Poor".Potential sources of bias mainly include differences in study population inclusion and exclusion criteria,diagnostic criteria for the disease,and consideration of,or adjustment for key variables known to be associated with gut microbiota composition.(2)Compared with the control group,the gut microbiota composition of patients with ASCVD was changed.And several differential gut microbiota were identified in patients with ASCVD.(3)Our findings indicate a shared alteration across multiple ASCVD for certain microbes.Desulfovibrio and Odoribacter are significantly enriched in the gut of patients with coronary heart disease and stroke,and Acidaminococcus is obviously enriched in the gut of patients with coronary heart disease and carotid atherosclerosis.(4)Comprehensive analysis showed that the present study could not provide strong evidence to support the difference of intestinal flora a diversity between ASCVD population and control group.Conclusion:ASCVD was related to gut microiota dysbiosis,and remodeling the homeostasis of gut microbiota is one of the potential therapeutic strategies to prevent and treat ASCVD.Part 2 Study the effect of Ginseng-Polygonum cuspidatum on the gut microbiota of AS model miceObjective:To verify the anti-atherosclerosis effect of Ginseng-Polygonum cuspidatum,and focus on the influence of Ginseng-Polygonum cuspidatum on the gut microbiota in AS model mice.Methods:A mouse model of AS was established by feeding ApoE knockout mice with a high-fat diet for 8 weeks.All AS model mice were randomly divided into six groups as follows:control,model,statin,low-dose group(GPL),medium-dose group(GPM),and high-dose group(GPH).Samples were collected,after 12 weeks of intervention.And the effects of Ginseng-Polygonum cuspidatum on lipid levels,inflammatory factors,aortic plaque area,gut barrier function,and gut microbiota composition in AS model mice were evaluated.Results:(1)Compared with the model group,Ginseng-Polygonum cuspidatum decreased the serum low density lipoprotein cholesterol,high density lipoprotein cholesterol,monocyte chemotactic protein-1,monocyte chemotactic protein-3,interleukin 2 and Eotaxin contents,and decreased the plaque area of aorta.(2)Compared with the model group,Ginseng-Polygonum cuspidatum increased the number of goblet cells and promoted the expression of tight junction proteins ZO-1 and Occludin in the colon,thereby repairing the damaged intestinal barrier.(3)Ginseng-Polygonum cuspidatum improved the disturbed gut microbiota in AS model mice.At the species level,a total of 25 gut microbiota were significantly regulated by the low,medium and high dose groups of Ginseng-Polygonum cuspidatum.Spearman correlation analysis showed that Bacteroides plebeius,Parabacteroides goldsteinii,and Eubacterium eligens were significantly negatively correlated with lipid or inflammatory factors,and they were significantly up-regulated by Ginseng-Polygonum cuspidatum.Roseburia faecis,Roseburia intestinalis,Bifidobacterium longum,Fusicatenibacter saccharivorans,Ruminococcus torques,Bacteroides vulgatus,Faecalibacterium prausnitzii,and Escherichia coli were positively correlated with lipid factors,and they were significantly down-regulated by Ginseng-Polygonum cuspidatum.(4)LEfSe analysis identified 7 core gut microbiota in AS model mice.And Acutalibacter muris,Collinsella massiliensis,Lactobacillus johnsonii,Helicobacter japonicus were positively correlated with LDL-C,MCP-1,or MCP-3.It is speculated that these bacterial species may be potential pathological predictors of AS.Moreover,the relative abundance of Collinsella massiliensis was decreased in low,medium and high dose groups of Ginseng-Polygonum cuspidatum.Conclusion:Ginseng-Polygonum cuspidatum herb pair could improve the levels of serum lipid and inflammation indicators,inhibit aortic plaque formation,alleviate intestinal barrier integrity,as well as modulate gut dysbiosis in AS model mice.Part 3 Study on the effects of Ginseng-Polygonum cuspidatum on metabolites in cecum of AS miceObjective:To identify the core differential metabolites regulated by Ginseng-Polygonum cuspidatum by analyzing the changes of metabolites in the cecum of mice in each group.Thus,to speculate on the possible metabolic pathways influenced by Ginseng-Polygonum cuspidatum.Methods:Based on the part 2,cecal contents of mice in each group were collected.Metabolite contents of mice in each group were determined by untargeted metabolomics analyses.And MetaboAnalyst 5.0 online analysis tool was used to analyze related metabolic pathways.Results:(1)Compared to model group,Ginseng-Polygonum cuspidatum significantly regulated various metabolites in the AS model mice.Ginseng-Polygonum cuspidatum in the low,medium and high dose groups co-regulated 22 differential metabolites.It showed that the metabolites including N-Carbamoyl-2-amino-2-(4-hydroxyphenyl)acetic acid,Montecristin,4-Methoxybenzyl O-(2-sulfoglucoside),and 20-Hydroxyeicosatetraenoic acid were positively correlated with lipid and inflammatory indicators,and they were significantly down-regulated by Ginseng-Polygonum cuspidatum.While the metabolites including Ascorbyl palmitate,Dopamine,and 4-Oxo-4-(3-pyridyl)-butanamide were negatively correlated with inflammatory factors,and they were significantly up-regulated by Ginseng-Polygonum cuspidatum.In addition,it was found that there was a significantly correlation between differential bacteria of the gut microbiota and differential metabolites.(2)KEGG pathway enrichment analysis showed that glycerophospholipid metabolism and niacin and nicotinamide metabolism pathways were significantly influenced by Ginseng-Polygonum cuspidatum.LysoPA(0:0/1 8:0)and 1-Methylnicotinamide played an important node role,respectively.Conclusion:It was found that Ginseng-Polygonum cuspidatum herb pair had a certain effect on the metabolites and metabolic pathways in the AS model mice.Ginseng-Polygonum cuspidatum herb pair may modulate the levels of LysoPA(0:0/18:0),1-Methylnicotinamide,and other metabolites in the AS model mice.And Ginseng-Polygonum cuspidatum herb pair may improve AS by regulating LysoPA(0:0/18:0),1-Methylnicotinamide and other metabolites,thereby affecting glycerol phospholipid metabolism and niacin and niacinamide metabolic pathways.Part 4 Effects of fecal microbiota transplantation(FMT)on AS model miceObjective:To clarify the role of the gut microbiota in the treatment of AS with Ginseng-Polygonum cuspidatum herb pair by fecal microbiota transplantation.Methods:In this fecal microbiota transplantation study,the microbiota donors were mice in the Model group and the GPH group in the Part 2 study.Healthy male ApoE-/-mice were selected as receptors.And the mice were randomly divided into two groups:the model fecal microbiota transplantation group(FMT-Mod),and the GPH fecal microbiota transplantation group(FMT-GPH).Samples from fecal transplant recipient mice were collected after 12 weeks intervention.Serum lipids,inflammatory factors,aortic plaque area,gut barrier function,and cecum metabolites were detected.Results:Compared with the FMT-Model group,the levels of TG,LDL-C,MCP-1 and TNFa in FMT-GPH group mice were significantly decreased,and the aortic plaque area was significantly decreased.FMT-GPH increased the number of goblet cells and promoted the expression of tight junction proteins ZO-1 and Occludin in the colon.FMT-GPH also significantly reduced the levels of the LysoPA(0:0/18:0),while increased the levels of 1-Methylnicotinamide.Conclusion:FMT decreased the levels of serum lipid and inflammatory indicators,decreased the aortic plaque,alleviated the intestinal barrier integrity,and regulated the levels of LysoPA(0:0/18:0)and 1 Methylnicotinamide in AS model mice.It was proved that the anti-atherosclerosis effect of Ginseng-Polygonum cuspidatum herb pair was related to the regulation of gut microbiota structure. |
PDF Full Text Request