Liu Quanzhen, Luo Zijie, Wu Yanjuan, Gan Qiming, Zhang Nuofu, Wu Kang
State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510160, Guangdong, China.
Nanshan School, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China.
Clin Rheumatol. 2025 Jun 12. doi: 10.1007/s10067-025-07526-5.
INTRODUCTION: Limited studies have explored the potential link between gut microbiota and eosinophilic granulomatosis with polyangiitis (EGPA), and the specific inflammatory cytokines involved in EGPA remain controversial. Additionally, the causal relationships between gut microbiota, inflammatory cytokines, and EGPA subtypes, as well as whether inflammatory cytokines mediate these effects, are not well understood. OBJECTIVES: We aim to investigate the causal effects of gut microbiota and inflammatory cytokines on the subtypes of EGPA and to elucidate the mediating role of inflammatory cytokines in this relationship. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using data from large-scale genome-wide association studies (GWAS) on gut microbiota, 91 inflammatory cytokines, and EGPA subtypes (ANCA/MPO ( +) EGPA and ANCA/MPO ( -) EGPA). A bidirectional MR analysis was performed to exclude the influence of EGPA subtypes on gut microbiota. Then, we explored the mediating role of inflammatory cytokines. The primary analysis employed the inverse-variance-weighted method, supplemented by MR-Egger, weighted median, weighted mode, and simple mode analyses. We used the Steiger test to address reverse causality, Cochran's Q statistic to evaluate heterogeneity, and the MR-PRESSO outlier detection test to identify and mitigate horizontal pleiotropy. RESULTS: For ANCA/MPO ( +) EGPA, we identified 12 gut microbiota (5 positive, 7 negative) and three circulating inflammatory cytokines (1 positive, 2 negative) with causal effects. Specifically, the genus Ruminococcus1 was a potential risk factor (OR, 1.052; 95% CI, 1.019-1.087, P = 0.002), while Eubacterium nodatum showed a protective effect (OR, 0.979; 95% CI, 0.966-0.991, P = 0.0009). IL-1α was associated with an increased risk (OR, 1.029; 95% CI, 1.010-1.049, P = 0.003), whereas leukemia inhibitory factor had a mitigating effect (OR, 0.963; 95% CI, 0.942-0.985, P = 0.001). For ANCA/MPO ( -) EGPA, we identified seven gut microbiota (2 positive, 5 negative) and six circulating inflammatory cytokines (5 positive, 1 negative) with causal effects. The family Bacteroidaceae showed a protective effect (OR, 0.939; 95% CI, 0.894-0.986, P = 0.01), whereas Ruminococcus1 was a risk factor (OR, 1.057; 95% CI, 1.009-1.108, P = 0.02). IL-2 (OR, 1.043; 95% CI, 1.009-1.077, P = 0.011), FGF 19 (OR, 1.044; 95% CI, 1.016-1.073, P = 0.002), and CXCL11 (OR, 1.035; 95% CI, 1.010-1.060, P = 0.005) were linked to increased risk. We also observed that the genus Parasutterella may mediate risk for ANCA/MPO ( +) EGPA by reducing leukemia inhibitory factor, accounting for a 21.4% mediating effect. No significant heterogeneity of instrumental variables or horizontal pleiotropy was detected. CONCLUSION: This pioneering MR study bridges a significant gap by elucidating the relationship between gut microbiota, inflammatory cytokines, and EGPA subtypes. It highlights novel mechanisms in autoimmune disease and suggests new therapeutic targets for clinical intervention. Future studies should focus on further elucidating the detailed mechanisms involved. Key Points • The underlying mechanism of EGPA remains elusive, leading to a high relapse rate after treatment, but without adequate attention from studies • Our research bridges this knowledge gap by investigating the novel mechanism regarding gut microbiota-inflammatory cytokines-EGPA subtypes • Mendelian randomization and mediation analysis offer robust approaches to uncover potential mechanisms, mitigating the biases inherent in observational studies • This is the first MR to identify potential novel drug targets for EGPA, and suggest that the genus Parasutterella may heighten the risk for ANCA/MPO ( +) EGPA by modulating the levels of leukemia inhibitory factor.
引言：关于肠道微生物群与嗜酸性肉芽肿性多血管炎（EGPA）之间潜在联系的研究有限，且EGPA中涉及的特定炎性细胞因子仍存在争议。此外，肠道微生物群、炎性细胞因子与EGPA亚型之间的因果关系，以及炎性细胞因子是否介导这些作用，目前尚不清楚。 目的：我们旨在研究肠道微生物群和炎性细胞因子对EGPA亚型的因果效应，并阐明炎性细胞因子在这种关系中的中介作用。 方法：我们使用来自大规模全基因组关联研究（GWAS）的数据，对肠道微生物群、91种炎性细胞因子和EGPA亚型（抗中性粒细胞胞浆抗体/髓过氧化物酶（+）EGPA和抗中性粒细胞胞浆抗体/髓过氧化物酶（-）EGPA）进行了两样本孟德尔随机化（MR）分析。进行了双向MR分析以排除EGPA亚型对肠道微生物群的影响。然后，我们探讨了炎性细胞因子的中介作用。主要分析采用逆方差加权法，并辅以MR-Egger、加权中位数、加权模式和简单模式分析。我们使用Steiger检验来解决反向因果关系，使用Cochran's Q统计量来评估异质性，并使用MR-PRESSO离群值检测检验来识别和减轻水平多效性。 结果：对于抗中性粒细胞胞浆抗体/髓过氧化物酶（+）EGPA，我们确定了12种具有因果效应的肠道微生物群（5种阳性，7种阴性）和三种循环炎性细胞因子（1种阳性，2种阴性）。具体而言，瘤胃球菌属1是一个潜在的危险因素（OR，1.052；95%CI，1.019-1.087，P = 0.002），而结节真杆菌显示出保护作用（OR，0.979；95%CI，0.966-0.991，P = 0.0009）。白细胞介素-1α与风险增加相关（OR，1.029；95%CI，1.010-1.049，P = 0.003），而白血病抑制因子具有缓解作用（OR，0.963；95%CI，0.942-0.985，P = 0.001）。对于抗中性粒细胞胞浆抗体/髓过氧化物酶（-）EGPA，我们确定了7种具有因果效应的肠道微生物群（2种阳性, 5种阴性）和6种循环炎性细胞因子（5种阳性, 1种阴性）。拟杆菌科显示出保护作用（OR，0.939；95%CI，0.894-0.986，P = 0.01），而瘤胃球菌属1是一个危险因素（OR，1.057；95%CI，1.009-1.108, P = 0.02）。白细胞介素-2（OR，1.043；95%CI，1.
Zhonghua Shao Shang Yu Chuang Mian Xiu Fu Za Zhi. 2025-6-20
Medicine (Baltimore). 2025-5-30
J Affect Disord. 2024-7-15
J Allergy Clin Immunol. 2023-6
Autoimmun Rev. 2023-1
Zotero 插件