Background A transmissible agent has long been suspected in the pathogenesis of SLE, yet the potential contribution of the human intestinal microbiome has been little examined. We therefore characterized the gut microbiota of patients with SLE, with special interest in those with lupus nephritis (LN).

Methods Blood and fecal samples from SLE patients were obtained, with strict inclusion/exclusion of criteria. Fecal 16S rDNA sequencing, as well as cytokine and autoantibody assays were performed. In addition, sera from two independent lupus cohorts were studied for validation. Biomarkers of gut leakiness were assessed.

Results Compared to controls, the intestinal microbiome from SLE patients (n=61) showed decreased species richness diversity with reductions in taxonomic complexity most pronounced in those with high disease activity. Notably, SLE patients had an overall 5-fold greater representation of a species in the Lachnospiracaea family of obligate anaerobic Gram-positive cocci, with reciprocal contractions of two other commensal species with putative protective properties. Abundance of the Lachnospiracaea species correlated with serum IgG to a cell wall component, postulated to represent a lipoglycan, from a strain of this same species (p=0.002, n=61, Spearman) but not with 7 other strains. There was also a significant direct correlation between SLEDAI scores and levels of these circulating anti-strain IgG antibodies (p=0.02, n=48). Levels of antibodies to strain-specific bacterial antigen, treated with RNAse/DNAse/proteinase K, 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 serum IgG 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 levels. High titers of these anti-bacterial antibodies were associated with active Class III, IV and V (overlap) LN (Cohort 3).

Conclusions These findings suggest a novel paradigm for the pathogenesis of LN in which a common intestinal commensal bacteria may contribute to the immune-complex mediated disease process, with features akin to poststreptococcal GN but without outward signs and symptoms of clinical infection.

Acknowledgements Judith and Stuart Colton Foundation, NIAMS- P50 AR070591.