DataSheet_1_Association between gut microbiota and NAFLD/NASH: a bidirectional two-sample Mendelian randomization study.docx

BackgroundRecent studies have suggested a relationship between gut microbiota and non-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). However, the nature and direction of this potential causal relationship are still unclear. This study used two-sample Mendelian randomization (MR) to clarify the potential causal links.
MethodsSummary-level Genome-Wide Association Studies (GWAS) statistical data for gut microbiota and NAFLD/NASH were obtained from MiBioGen and FinnGen respectively. The MR analyses were performed mainly using the inverse-variance weighted (IVW) method, with sensitivity analyses conducted to verify the robustness. Additionally, reverse MR analyses were performed to examine any potential reverse causal associations.
ResultsOur analysis, primarily based on the IVW method, strongly supports the existence of causal relationships between four microbial taxa and NAFLD, and four taxa with NASH. Specifically, associations were observed between Enterobacteriales (P =0.04), Enterobacteriaceae (P =0.04), Lachnospiraceae UCG-004 (P =0.02), and Prevotella9 (P =0.04) and increased risk of NAFLD. Dorea (P =0.03) and Veillonella (P =0.04) could increase the risks of NASH while Oscillospira (P =0.04) and Ruminococcaceae UCG-013 (P=0.005) could decrease them. We also identified that NAFLD was found to potentially cause an increased abundance in Holdemania (P =0.007) and Ruminococcus2 (P =0.002). However, we found no evidence of reverse causation in the microbial taxa associations with NASH.
ConclusionThis study identified several specific gut microbiota that are causally related to NAFLD and NASH. Observations herein may provide promising theoretical groundwork for potential prevention and treatment strategies for NAFLD and its progression to NASH in future.

研究背景 近期已有研究提示肠道微生物组（gut microbiota）与非酒精性脂肪性肝病（non-alcoholic fatty liver disease, NAFLD）/非酒精性脂肪性肝炎（nonalcoholic steatohepatitis, NASH）存在关联。但二者潜在因果关联的本质与方向仍未明确。本研究采用两样本孟德尔随机化（two-sample Mendelian randomization, MR）方法，旨在阐明二者间潜在的因果联系。
研究方法 本研究分别从MiBioGen与FinnGen数据库获取肠道微生物组及NAFLD/NASH的汇总级全基因组关联研究（Summary-level Genome-Wide Association Studies, GWAS）统计数据。主要采用逆方差加权（inverse-variance weighted, IVW）方法开展孟德尔随机化分析，并通过敏感性分析验证结果的稳健性。此外，还进行了反向孟德尔随机化分析，以检测是否存在潜在的反向因果关联。
研究结果 本研究以逆方差加权方法为主要分析手段，结果强烈支持4种微生物类群与NAFLD、4种微生物类群与NASH之间存在因果关联。具体而言，肠杆菌目（Enterobacteriales, P=0.04）、肠杆菌科（Enterobacteriaceae, P=0.04）、毛螺菌科UCG-004（Lachnospiraceae UCG-004, P=0.02）及普雷沃氏菌属9（Prevotella9, P=0.04）与NAFLD发病风险升高相关。多雷菌属（Dorea, P=0.03）与韦荣球菌属（Veillonella, P=0.04）可增加NASH的发病风险，而颤螺菌属（Oscillospira, P=0.04）与瘤胃球菌科UCG-013（Ruminococcaceae UCG-013, P=0.005）则可降低该风险。此外，本研究还发现NAFLD可能会导致霍尔德曼氏菌属（Holdemania, P=0.007）与瘤胃球菌属2（Ruminococcus2, P=0.002）的丰度升高。但未发现微生物类群与NASH之间存在反向因果关联的证据。
研究结论 本研究明确了数种与NAFLD及NASH存在因果关联的特异性肠道微生物类群。本研究结果可为未来NAFLD及其进展为NASH的潜在防治策略提供有价值的理论基础。