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Several studies indicated that SLE patients had dysbiosis of gut microbiome and decreased species richness ( 8, 9). One possible explanation was that the presence of commensal gut microbiome influenced the autoimmune responses to nuclear antigens ( 7). The dysbiosis of gut microbiome affected immune responses, which contributed to the occurrence of autoimmune diseases ( 6). A study demonstrated that the gut microbiome was related to the dynamics of human immune cells, suggesting that the gut microbiome drove the modulation of the immune system ( 5). The intestinal microbiota plays a critical role in the maturation of the host immune response and provide protection against pathogen overgrowth ( 4). Recently, the causal link between the gut microbiome composition and SLE risk has attracted widespread attention. Therefore, it is imperative to explore the etiology of SLE to facilitate the development of treatment strategies with low damage or even no side effects. Long-term use of immunosuppressants weakens the immunity and results in severe infections ( 3). The current treatment strategy is mainly the use of non-selective immunosuppressive agents. In addition, ultraviolet light and infections induce DNA damage and apoptosis which increase exposure to autoantigens are potential triggers for SLE as well ( 2). Genetic, hormonal, and environmental factors interact in susceptible individuals, resulting in autoantibodies deposition and abnormal production of proinflammatory cytokines ( 1). Loss of tolerance to autoantigens is one of the hallmarks of SLE.

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Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease involving multiple organs, and it presents with a range of clinical symptoms, including skin rash, pericarditis, nephritis, and neurological and hematological involvement. This study support that there are beneficial or detrimental causal effects of gut microbiome components on SLE risk.

However, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) detected significant horizontal pleiotropy between the instrumental variables of Ruminiclostridium6 and outcome. Based on the genome-wide statistical significance threshold, the results showed that Actinobacteria might reduce the SLE risk. The estimates of MR Egger suggested that genetically predicted Ruminiclostridium6 was negatively associated with SLE. The results of weighted median method supported that Bacilli, Lactobacillales, and Eggerthella were risk factors for SLE and Bacillales and Coprobacter served as protective factors for SLE. The inverse variance weighted (IVW) method suggested that Bacilli and Lactobacillales were positively correlated with the risk of SLE and Bacillales, Coprobacter and Lachnospira were negatively correlated with SLE risk. Based on the locus-wide significance level, the results indicated that there were causal effects of gut microbiome components on SLE risk. To obtain a comprehensive conclusion, the other group where SNPs were smaller than the locus-wide significance level (1 × 10 -5) were selected as instrumental variables. A group of single nucleotide polymorphisms (SNPs) that less than the genome-wide statistical significance threshold (5 × 10 -8) served as instrumental variables. The present study used publicly available genome-wide association study (GWAS) summary data to perform two-sample Mendelian randomization (MR), aiming to examine the causal links between gut microbiome and SLE. However, whether the association is causal remains unclear. The observational association between gut microbiome and systemic lupus erythematosus (SLE) has been well documented. 6Department of Nephrology, Second Affiliated Hospital of Anhui Medical University, Hefei, China.

5Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.4School of Public Health, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.3Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University Medical College, Suzhou, China.2Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.1Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.Kun Xiang 1,2†, Peng Wang 3†, Zhiwei Xu 4†, Yu-Qian Hu 1,2, Yi-Sheng He 1,2, Yue Chen 1,2, Ya-Ting Feng 1,2, Kang-Jia Yin 1,2, Ji-Xiang Huang 1,2, Jie Wang 1,2, Zheng-Dong Wu 1,2, Xiao-Ke Yang 5, De-Guang Wang 6, Dong-Qing Ye 1,2* and Hai-Feng Pan 1,2*