DataSheet_1_Bidirectional effects of oral anticoagulants on gut microbiota in patients with atrial fibrillation.xlsx

BackgroundThe imbalance of gut microbiota (GM) is associated with a higher risk of thrombosis in patients with atrial fibrillation (AF). Oral anticoagulants (OACs) have been found to significantly reduce the risk of thromboembolism and increase the risk of bleeding. However, the OAC-induced alterations in gut microbiota in patients with AF remain elusive.
MethodsIn this study, the microbial composition in 42 AF patients who received long-term OAC treatment (AF-OAC group), 47 AF patients who did not (AF group), and 40 volunteers with the risk of AF (control group) were analyzed by 16S rRNA gene sequencing of fecal bacterial DNA. The metagenomic functional prediction of major bacterial taxa was performed using the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) software package.
ResultsThe gut microbiota differed between the AF-OAC and AF groups. The abundance of Bifidobacterium and Lactobacillus decreased in the two disease groups at the genus level, but OACs treatment mitigated the decreasing tendency and increased beneficial bacterial genera, such as Megamonas. In addition, OACs reduced the abundance of pro-inflammatory taxa on the genus Ruminococcus but increased certain potential pathogenic taxa, such as genera Streptococcus, Escherichia-Shigella, and Klebsiella. The Subgroup Linear discriminant analysis effect size (LEfSe) analyses revealed that Bacteroidetes, Brucella, and Ochrobactrum were more abundant in the anticoagulated bleeding AF patients, Akkermansia and Faecalibacterium were more abundant in the non-anticoagulated-bleeding-AF patients. The neutrophil-to-lymphocyte ratio (NLR) was lower in the AF-OAC group compared with the AF group (P < 0.05). Ruminococcus was positively correlated with the NLR and negatively correlated with the CHA2DS2-VASc score (P < 0.05), and the OACs-enriched species (Megamonas and Actinobacteria) was positively correlated with the prothrombin time (PT) (P < 0.05). Ruminococcus and Roseburia were negatively associated with bleeding events (P < 0.05).
ConclusionsOur study suggested that OACs might benefit AF patients by reducing the inflammatory response and modulating the composition and abundance of gut microbiota. In particular, OACs increased the abundance of some gut microbiota involved in bleeding and gastrointestinal dysfunction indicating that the exogenous supplementation with Faecalibacterium and Akkermansia might be a prophylactic strategy for AF-OAC patients to lower the risk of bleeding after anticoagulation.

研究背景：肠道菌群（gut microbiota, GM）失衡与心房颤动（atrial fibrillation, AF）患者的血栓形成风险升高显著相关。现有研究证实，口服抗凝剂（oral anticoagulants, OACs）可显著降低血栓栓塞风险，但同时会升高出血风险。然而，口服抗凝剂对心房颤动患者肠道菌群的调控作用仍尚不明确。研究方法：本研究收集了长期接受口服抗凝剂治疗的42例心房颤动患者（AF-OAC组）、未接受抗凝治疗的47例心房颤动患者（AF组）以及40例存在心房颤动风险的志愿者（对照组）的粪便样本，通过对粪便细菌DNA进行16S rRNA基因测序，分析三组受试者的菌群组成；并采用未观察状态重建系统发育群落分析（Phylogenetic Investigation of Communities by Reconstruction of Unobserved States, PICRUSt）软件包，对主要细菌类群进行宏基因组功能预测。研究结果：AF-OAC组与AF组患者的肠道菌群组成存在显著差异。在属水平上，双歧杆菌属（Bifidobacterium）与乳杆菌属（Lactobacillus）在两个疾病组中丰度均出现下降；而口服抗凝剂治疗可缓解这一下降趋势，并上调巨单胞菌属（Megamonas）等有益菌属的丰度。此外，口服抗凝剂可降低促炎菌属瘤胃球菌属（Ruminococcus）的丰度，但同时会增加链球菌属（Streptococcus）、埃希菌-志贺菌属（Escherichia-Shigella）及克雷伯菌属（Klebsiella）等潜在致病菌属的丰度。亚组线性判别分析效应大小（Linear discriminant analysis effect size, LEfSe）分析结果显示，在接受抗凝治疗后发生出血的心房颤动患者中，拟杆菌门（Bacteroidetes）、布鲁菌属（Brucella）及苍白杆菌属（Ochrobactrum）的丰度更高；而在未接受抗凝治疗的出血型心房颤动患者中，嗜黏蛋白阿克曼菌属（Akkermansia）与粪杆菌属（Faecalibacterium）的丰度更高。AF-OAC组的中性粒细胞与淋巴细胞比值（neutrophil-to-lymphocyte ratio, NLR）显著低于AF组（P < 0.05）。瘤胃球菌属与NLR呈正相关，而与CHA2DS2-VASc评分呈负相关（P < 0.05）；口服抗凝剂富集的细菌类群（巨单胞菌属与放线菌门（Actinobacteria））与凝血酶原时间（prothrombin time, PT）呈正相关（P < 0.05）。瘤胃球菌属与罗氏菌属（Roseburia）均与出血事件呈负相关（P < 0.05）。研究结论：本研究表明，口服抗凝剂或可通过减轻炎症反应、调控肠道菌群的组成与丰度，使心房颤动患者获益。值得注意的是，口服抗凝剂会增加部分与出血及胃肠道功能紊乱相关的肠道菌群丰度，提示外源性补充粪杆菌属与嗜黏蛋白阿克曼菌属，或可成为预防接受抗凝治疗的心房颤动患者抗凝后出血风险的潜在策略。