肠道菌群及其代谢产物苯乙酰谷氨酰胺在慢性心力衰竭患者中的变化研究

• 作者： 张振东 ¹ 蔡斌 ² 王宏伟 ^1,2 乔增勇 ^1,2
• 作者单位：
  1.  232000 安徽省淮南市，安徽理工大学

  2.  201400 上海市，上海交通大学附属第六人民医院南院心内科
• 提交时间：2023-06-08

摘要: 背景　慢性心力衰竭（CHF）是各种心血管疾病的严重表现或末期阶段，肠道菌群及其代谢产物在心力衰竭的病理过程中起重要作用。越来越多证据表明，肠道菌群失调及其代谢产物紊乱可导致细菌移位、释放介质、炎性反应等，进而加重CHF病情。目的　分析肠道菌群及其代谢产物苯乙酰谷氨酰胺（PAGln）在CHF患者中的变化，探讨肠道微生物在心力衰竭中所发挥的作用。方法　选取上海交通大学附属第六人民医院南院心内科收治的心力衰竭患者58例为CHF组，另选取具有相同CHF危险因素但没有CHF临床症状表现及既往病史的患者46例为Control组，利用16SrRNA测序技术对两组患者的肠道菌群多样性和丰度进行分析。采用液相色谱串联质谱法（LC-MS/MS）检测两组标本血浆中的PAGln水平。结果　CHF组左心室收缩末期内径（LVESD）、左心室舒张末期内径（LVEDD）、脑钠肽（BNP）、PAGln均高于Control组，左心室射血分数（LVEF）低于Control组（P<0.05）。BNP和PAGln水平诊断CHF患者的曲线下面积（AUC）分别为0.995、0.913。Venn图表明，CHF组特有OTUs数目少于Control组。多样性分析表明，CHF组Chao1指数低于Control组（P<0.05）；多样性分析表明，两组的肠道菌群总体结构存在差异。属水平上，CHF组埃希氏-志贺菌属（Escherichia-Shigella）、巨单胞菌属（Megamonas）、克雷伯氏菌属（Klebsiella）、双歧杆菌属（Bifidobacterium）、副拟杆菌（Parabacteroides）、罗姆布茨菌（Romboutsia）相对丰度高于Control组（P<0.05），Solimonas和多尔氏菌属（Dorea）相对丰度低于Control组（P<0.05）。LEfSe分析结果显示毛螺菌科（Lachnospiraceae）、Solimonadaceae、Solimonas、Dorea、伯克氏菌科（Burkholderiaceae）在Control组中升高（P<0.05），肠杆菌科（Enterobacteriaceae）、埃希氏菌属（Escherichia）、Bifidobacterium、双歧杆菌科（Bifidobacteriaceae）、Klebsiella、乳杆菌科（Lactobacillaceae）、乳杆菌属（Lactobacillus）、巨单胞菌属（Megamonas）、理研菌科（Rikenellaceae）、另枝菌属（Alistipes）、Parabacteroides、盲肠坦纳菌科（Tannerellaceae）在CHF组升高（P<0.05）。典型相关分析（CCA）表明，BNP、PAGln、LVEDD、LVESD与CHF组菌群显著相关，其中BNP对群落变化影响最大。相关性分析表明，Escherichia-Shigella与BNP和PAGln呈正相关（P<0.05）；拟杆菌属（Bacteroides）与BNP呈负相关（P<0.05）；Romboutsia、梭杆菌属（Fusobacterium）、内考拉杆菌属（Phascolarctobacterium）与BNP和PAGln呈负相关（P<0.05）。结论　CHF患者肠道菌群结构组成与具有相同合并疾病但没有CHF临床症状表现及既往病史的患者明显不同，多样性下降，肠道致病菌丰度明显升高，可能导致CHF患者体内PAGln水平上升，参与CHF的发生发展。

Abstract: Background The intestinal flora and its metabolites play an important role in the pathology of chronic heart failure（CHF），which is a severe manifestation or terminal stage of various cardiovascular diseases. Increasing evidence has shown that dysbiosis of the intestinal flora and its metabolites can lead to bacterial translocation，release of mediators，inflammatory response and consequently aggravation of CHF. Objective To analyze the changes of intestinal flora and its metabolite phenylacetylglutamine （PAGln） in patients with CHF and explore the role played by gut microbiota in heart failure. Methods A total of58 patients with heart failure admitted to the Department of Cardiology of the South Branch of the Sixth People's Hospital of Shanghai Jiaotong University were selected as the CHF group，and 46 patients with the same CHF risk factors but without clinical symptoms and past medical history of CHF were selected as the control group. The abundance and diversity of intestinal flora in the two groups were analyzed using 16S rRNA sequencing. Liquid chromatography with tandem mass spectrometry （LC-MS/MS） was used to detect PAGln concentrations in the plasma of samples from both two groups. Results The left ventricular end-systolic diameter （LVESD），left ventricular end-diastolic diameter （LVEDD），brain natriuretic peptide （BNP），and PAGln in the CHF group were higher than the control group，and the left ventricular ejection fraction （LVEF） was lower than the control group （P<0.05）. The area under curve （AUC） of BNP and PAGln levels for the diagnosisof CHF patients was 0.995 and 0.913，respectively. Venn diagram showed that the number of OTUs specific to the CHF group was less than the control group. Alpha diversity analysis showed that the Chao 1 index was lower in the CHF group than the control group （P<0.05）. diversity analysis showed that the overall structure of the intestinal flora differed between the two groups. At the genus level，the relative abundances of Escherichia-Shigella，Megamonas，Klebsiella，Bifidobacterium，Parabacteroides，and Romboutsia were higher in the CHF group than the control group （P<0.05），and the relative abundances of Solimonas and Dorea were lower than the control group （P<0.05）. The results of LEfSe analysis showed that Lachnospiraceae，Solimonadaceae，Solimonas，Dorea，and Burkholderiaceae were elevated in the control group （P<0.05），and Enterobacteriaceae，Escherichia Bifidobacterium，Bifidobacteriaceae，Klebsiella，Lactobacillaceae，Lactobacillus，Megamonas，Rikenellaceae，Alistipes，Parabacteroides，and Tannerellaceae were elevated in the CHF group （P<0.05）. Typical correlation analysis （CCA） showed that BNP，PAGln，LVEDD，and LVESD were significantly correlated with the CHF group，with BNP having the greatest effect on community changes. Correlation analysis showed that Escherichia-Shigella was positively correlated with BNP and PAGln；Bacteroides was negatively correlated with BNP；Romboutsia，Fusobacterium，and Phascolarctobacterium were negatively correlated with BNP and PAGln. Conclusion 　The structural composition of the intestinal flora in patients with CHF was significantly different from the patients with the same co-morbidities but without clinical manifestations and previous medical history of CHF，with a decrease in flora diversity and a significant increase in the abundance of pathogenic intestinal bacteria，which may lead to an increase in the level of PAGln in CHF patients and participate in the development of CHF.

• 分类： 医学、药学 >> 临床医学
• 引用： ChinaXiv:202306.00071 (或此版本 ChinaXiv:202306.00071V1)
  DOI:10.12114/j.issn.1007-9572.2023.0166
  CSTR:32003.36.ChinaXiv.202306.00071.V1
• 推荐引用方式： 张振东,蔡斌,王宏伟,乔增勇.(2023).肠道菌群及其代谢产物苯乙酰谷氨酰胺在慢性心力衰竭患者中的变化研究.中国全科医学.doi:10.12114/j.issn.1007-9572.2023.0166 (点此复制)