Objective Whereas genetic susceptibility for Systemic Lupus Erythematosus (SLE) has been well explored, the triggers for clinical disease flares remain elusive. To investigate relationships between microbiota community resilience and disease activity, we performed the first longitudinal analyses of lupus gut-microbiota communities.

Methods In an observational study, taxonomic analyses, including multivariate analysis of b- diversity, assessed time-dependent alterations in fecal communities from patients and healthy controls. From blooms, strains were isolated with genomes and associated glycans analyzed.

Results Multivariate analyses documented that, unlike healthy controls, significant temporal community-wide ecological microbiota instability was common amongst in SLE patients, with transient intestinal growth spikes of several pathogenic species. Expansions of only the anaerobic commensal, Blautia (Ruminococcus) gnavus (RG) occurred at times of high-disease activity, and was detected in almost half of patients during lupus nephritis (LN) disease flares. Bulk RNA sequencing, from blood Paxgene tubes, demonstrated that patients with active LN and concurrent RG gut blooms have pathways of platelet activation, first documented in patients with sepsis. Whole genome sequence analysis of RG strains isolated during these flares documented 34 genes postulated to aid adaptation and expansion within a host with an inflammatory condition. Yet, the most specific feature for strains found during Lupus flares was the common expression of a novel type of cell wall-associated lipoglycan. These lipoglycans share conserved structural features documented by mass spectroscopy, and highly immunogenic repetitive antigenic- determinants, recognized by high-level serum IgG2 antibodies, that spontaneously arose, concurrent with RG blooms and lupus flares.¹Gut colonization with RG strains from LN patients induce high levels of IgG antibodies to lipoglycan and lupus autoantibodies in non autoimmune prone C57BL/6 mice, while RG strains from heathy donors do not.

Conclusions Our findings rationalize how blooms of the RG pathobiont may be common .drivers of clinical flares of often remitting-relapsing Lupus disease, by pathways that may be different from other forms of LN, and highlight the potential pathogenic properties and clinical impact of specific strains isolated from active Lupus nephritis patients. An antibody biomarker assay for the novel RG strain-associated lipoglycan could aid to earlier diagnosis of LN risk, and better therapeutic decision-making, whereas therapeutic targeting of pathobiont strains could provide a means to treat LN flares without the immunosuppression inherent to all current treatments.

Reference

1. Azzouz D, et al. Ann Rheum Dis 2023 (in press).