尽管肠道菌群对胃肠道腺癌的影响已为人所知，但肠道菌群与胃肠胰腺神经内分泌肿瘤（GEP-NEN）之间的相互作用仍知之甚少。因此，本研究旨在通过进行双向孟德尔随机化 (MR) 分析来确定肠道菌群与 GEP-NEN 之间的潜在因果关系。使用 MiBioGen 联盟的肠道微生物群的汇总统计数据进行了双样本 MR 分析以及来自 FinnGen 研究项目的 GEP-NEN。逆方差加权方法被用作主要分析方法。为了增强我们研究结果的稳健性，进行了多项敏感性测试，包括用于评估异质性的 Cochran's Q 检验、用于检测水平多效性的 MR-Egger 截距检验以及用于识别异常值和评估多效性偏差的 MR-PRESSO 检验。此外，还进行了留一分析以验证我们研究结果的一致性。 MR-Steiger 检验还用于确定肠道微生物群与 GEP-NEN 之间相关性的因果方向。最后，进行反向 MR 分析以评估肠道菌群和 GEP-NEN 之间的反向因果关系。我们鉴定了 42 个肠道微生物群，它们可能与 GEP-NEN 存在因果关系；在这些类群中，7、8、11 和 16 个类群分别与胰腺 NEN、结直肠 NEN、小肠 NEN 和胃 NEN 存在因果关系。经过错误发现率 (FDR) 校正后，我们发现广古菌与小肠 NEN 以及家族 XIII UCG-001 与胃 NEN 之间存在显着因果关系。敏感性分析证实了这些相关性的稳定性。在反向 MR 分析中，发现结直肠 NEN 和小肠 NEN 分别与肠道微生物群的 8 种和 6 种不同分类群的变异相关。经过 FDR 校正后，没有检测到 GEP-NEN 与肠道菌群之间存在显着的因果关系。本研究揭示了肠道菌群的某些分类群与 GEP-NEN 之间潜在的因果关系，从而为 GEP-NEN 的作用提供了新的视角。肠道菌群参与这些肿瘤的发展。这些见解可以提供筛查和预防这些疾病的创新方法。版权所有 © 2024 张、江、曹、徐、王、李和苗。

The interaction between the intestinal flora and gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) remains poorly understood, despite the known effect of the gut microbiota on gastrointestinal adenocarcinomas. Hence, the present research aimed to determine the potential causal correlation between the intestinal flora and GEP-NENs by conducting a bidirectional Mendelian randomization (MR) analysis.Two-sample MR analysis was conducted using the summary statistics of the gut microbiota from the MiBioGen consortium and those of GEP-NENs from the FinnGen research project. The inverse-variance weighted approach was utilized as the primary analytical method. To enhance the robustness of our findings, multiple sensitivity tests were performed, including Cochran's Q test for evaluating heterogeneity, the MR-Egger intercept test to detect horizontal pleiotropy, and the MR-PRESSO test to identify outliers and assess pleiotropy bias. Additionally, a leave-one-out analysis was performed to validate the consistency of our findings. The MR-Steiger test was also utilized to determine the causal direction in the correlation between the gut microbiota and GEP-NENs. Finally, a reverse MR analysis was performed to assess reverse causality between the intestinal flora and GEP-NENs.We identified 42 taxa of the gut microbiota that were potentially causally associated with GEP-NENs; of these taxa, 7, 8, 11, and 16 taxa were causally associated with pancreatic NENs, colorectal NENs, small intestinal NENs, and gastric NENs, respectively. After adjusting for false discovery rate (FDR) correction, we found significant causal links of Euryarchaeota with small intestinal NENs and Family XIII UCG-001 with gastric NENs. The sensitivity analyses confirmed the stability of these correlations. In the reverse MR analysis, colorectal NENs and small intestinal NENs were found to be associated with variations in 8 and 6 different taxa of the gut microbiota, respectively. After adjusting for FDR correction, no significant causal links were detected between GEP-NENs and the intestinal flora.The present study reveals a potential causal association between certain taxa of the intestinal flora and GEP-NENs, thus providing new perspectives regarding the role of the intestinal flora in the development of these tumors. These insights could provide innovative approaches to screen and prevent these diseases.Copyright © 2024 Zhang, Jiang, Cao, Xu, Wang, Li and Miao.