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Systemic lupus erythematosus (SLE), characterized by chronic inflammation and multi-organ damage, has been suggested to associate with gut dysbiosis, but knowledge is limited from small sample size and 16s rRNA-based studies. To shed new light on the role of microbiota in SLE development, we analyzed the fecal metagenome of 117 treatment-naive SLE patients and 115 sex- and age-matched healthy controls (HC) by deep-sequencing; in addition, 52 of the aforementioned patients have post-treatment fecal metagenome for comparison. We found significant differences in microbial composition and function between SLE and HC, revealing multiple plausible contributing bacterial species and metabolic pathways in SLE. In-depth SNP-based analysis revealed an oral-microbiome origin for two marker species, strengthening the importance of bacterial translocation in disease development. Lastly, we confirmed experimentally that peptides of SLE-enriched species mimicking autoantigens such as Sm and Fas could trigger autoimmune responses, suggesting a potential causal role of gut microbiota in SLE.

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