Background/Purpose: A transmissible agent has long been suspected in the pathogenesis of SLE, yet the potential contribution of members of the intestinal microbiome to the immune abnormalities in active SLE has not previously been investigated. We therefore characterized the gut microbiota of patients with SLE, with special interest in those with Lupus nephritis (LN), a clinical feature too commonly associated with great morbidity and early mortality.

Methods: Blood and fecal samples from SLE patients were obtained, with the exclusion of patients with selective IgA deficiency, or history of prior cytotoxic drugs, or antibiotics within four months. Fecal 16S rRNA next generation sequencing was performed. Sera samples were profiled for autoantibodies. In addition, sera from two independent lupus cohorts were studied for validation.

Results: Compared to controls, the intestinal microbiome from SLE patients (N=61) showed decreased species richness diversity. The microbiota of patients in clinical remission (based on SLEDAI) were most similar to healthy controls, while reductions in taxonomic complexity were most pronounced in those with high disease activity. Notably, SLE patients had an overall 5-fold greater representation of a particular species in the Blautia genus of the Lachnospiracaea family of obligate anaerobic Gram-positive cocci. There were reciprocal significant contractions of two other commensal species with putative protective properties. Abundance of the Lachnospiracaea species significantly correlated with serum IgG to a cell wall moiety from a strain of this same species (P=0.002, N=61, Spearman) but not with 7 other strains. There was also a significant correlation between the distribution of SLEDAI scores and levels of these circulating anti-strain IgG antibodies (P=0.02, N=48). Using bacterial antigen treated with DNAse/proteinase K, levels of IgG anti-strain antibodies were significantly higher in those with active nephritis at time of sampling compared to SLE without renal activity (Cohort 1 P=0.01 N=48; Cohort 2 P=0.006, N=28, Mann-Whitney). Levels of anti- strain antibodies also significantly correlated with high-titer serum IgG to native DNA (P<0.0001, N=27), and inversely correlated with C3 and C4 (each P<0.01, N=61). High titers of these anti-bacterial antibodies were found in patients with active Class III, IV and V LN (Cohort 3).

Conclusion: These findings suggest a novel paradigm for the pathogenesis of LN in which specific strains of common intestinal commensal bacteria contribute to the immune-complex mediated disease process responsible for glomerulonephritis (GN). This is reminiscent of poststreptococcal GN, although in LN the postulated intestinal bacterial dysbioses and microbial expansion appear to occur without outward signs and symptoms of clinical infection.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lupus-nephritis-is-linked-to-immunity-to-an-intestinal-commensal-lachnospiracaea-species/