肠道微生物群和炎性细胞因子与系统性红斑狼疮风险相关的遗传易感性：一项多组学研究。

Genetic liability to gut microbiota and inflammatory cytokines in relation to systemic lupus erythematosus risk: a multi-omics study.

作者信息

Lu Rui-Ling, Chen Yan-Ran, Yang Xu-Fa, Huang Xin-Yi, Liu Dong-Zhou, Hong Xiao-Ping

机构信息

Department of Rheumatology and Immunology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong, China.

Department of Rheumatology and Immunology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.

出版信息

Clin Rheumatol. 2025 May 7. doi: 10.1007/s10067-025-07435-7.

DOI:10.1007/s10067-025-07435-7

PMID:40332703

Abstract

OBJECTIVES

Systemic lupus erythematosus (SLE) has been associated with gut microbiota in some studies. There is no clear evidence that cytokines act as mediators.

METHODS

We first assessed the differences in gut microbiota between SLE patients and healthy controls using 16S rDNA sequencing. Subsequently, we used the summary statistics of gut microbiota, cytokines, and SLE from large genome-wide association studies. To explore the causal relationships between gut microbiota and SLE and identify potential mediating cytokines, we performed bidirectional Mendelian randomization analyses. Finally, the levels of potentially mediating cytokines were determined by ELISA.

RESULTS

Fecal 16S rDNA sequencing showed that there was gut microbiota disorder in SLE patients. Based on two-sample analysis, seven gut microbiota taxa were causally associated with SLE. SLE influenced the relative abundance of two gut microbiota taxa in our large-scale MR study. Mediation analyses revealed that the causal relationship between genus Lachnospiraceae UCG001 and SLE was exclusively mediated by fibroblast growth factor 19 (FGF19) levels and the causal relationship between order Lactobacillales and SLE was exclusively mediated by tumor necrosis factor receptor superfamily member 9 (TNFRSF9) levels. Elevated levels of FGF19 affected the association between the reduced relative abundance of the genus Coprobacter and SLE, mediating by a proportion of 10.64% (P = 0.030). Furthermore, ELISA showed that circulating TNFRSF9 and FGF19 levels were higher in SLE patients than healthy controls.

CONCLUSION

Our study demonstrated that there is a causal link between some gut microbiota taxa and SLE. In addition, we revealed possible mediating effects in this relationship. Key Points • We first demonstrate a causal association between gut microbiota, cytokines, and SLE comprehensively. • Our experiments also confirmed that TNFRSF9 and FGF19 may play a role in SLE. These results provide new ideas for microbiome-based investigation of new mechanisms and therapies for SLE.

摘要

目的

一些研究表明系统性红斑狼疮（SLE）与肠道微生物群有关。目前尚无明确证据表明细胞因子起介导作用。

方法

我们首先使用16S rDNA测序评估SLE患者与健康对照之间肠道微生物群的差异。随后，我们使用了来自大型全基因组关联研究的肠道微生物群、细胞因子和SLE的汇总统计数据。为了探索肠道微生物群与SLE之间的因果关系并确定潜在的介导细胞因子，我们进行了双向孟德尔随机化分析。最后，通过酶联免疫吸附测定法（ELISA）测定潜在介导细胞因子的水平。

结果

粪便16S rDNA测序显示SLE患者存在肠道微生物群紊乱。基于两样本分析，7种肠道微生物分类群与SLE存在因果关联。在我们的大规模孟德尔随机化研究中，SLE影响了两种肠道微生物分类群的相对丰度。中介分析显示，毛螺菌科UCG001属与SLE之间的因果关系完全由成纤维细胞生长因子19（FGF19）水平介导，乳杆菌目与SLE之间的因果关系完全由肿瘤坏死因子受体超家族成员9（TNFRSF9）水平介导。FGF19水平升高影响了粪杆菌属相对丰度降低与SLE之间的关联，介导比例为10.64%（P = 0.030）。此外，ELISA显示SLE患者循环中的TNFRSF9和FGF19水平高于健康对照。

结论

我们的研究表明一些肠道微生物分类群与SLE之间存在因果联系。此外，我们揭示了这种关系中可能的介导作用。要点•我们首次全面证明了肠道微生物群、细胞因子和SLE之间的因果关联。•我们的实验还证实TNFRSF9和FGF19可能在SLE中起作用。这些结果为基于微生物组的SLE新机制和治疗方法的研究提供了新思路。