Lupus disease flares are concordant with immune responses to blooms of lipoglycan-expressing Ruminococcus blautia gnavus strains arising from unstable gut microbiota communities

Abstract

Whereas genetic susceptibility for Systemic Lupus Erythematosus has been well explored, the precipitants for clinical disease flares remain a mystery. To investigate for dynamic-relationships between gut-microbial communities and Lupus disease activity, we performed taxonomic surveys of fecal 16S rRNA gene amplicon-libraries from Lupus patients and healthy volunteers, obtained at serial timepoints over many months to several years. Individual Lupus patients commonly displayed imbalances in alpha and beta microbiota-diversity, which were uniquely different from healthy individuals as well as from other Lupus patients. Moreover, multivariate analysis of sequential Lupus libraries documented community-wide ecological microbiota instability overtime, most pronounced in patients with Lupus Nephritis LN), a severe form associated with worse prognosis. Lupus gut communities displayed transient spikes of pathogenic bacterial species, with by far the most prevalent being blooms of Ruminococcus blautia gnavus (RG), occurring in nearly half of LN patients often concordant with disease activity flares. RG strains isolated during disease flares, but not those isolated from healthy individuals or patients with inflammatory bowel disease, commonly expressed a novel, highly immunogenic cell wall-associated lipoglycan with conserved structural features that include a diacyl glycerol anchor. Cross-reactive antigenic determinants on these lipoglycans were recognized by murine monoclonal antibodies, and by spontaneously arising Lupus serum IgG antibodies with peak serum antibody responses also concordant with RG blooms. As SLE is frequently characterized by remitting-relapsing disease, despite appropriate treatment, we speculate that gut blooms of pathogenic bacteria, that impair gut barrier function and stoke systemic inflammation, directly contribute to immunopathogenesis.