{
  "abstract": "For more than a century, certain bacterial infections that breach skin or mucosal barriers have been known to act as triggers of autoimmune syndromes, including rheumatic fever and post-streptococcal glomerulonephritis. Yet only recently have imbalances within our microbiota commensal communities been suspected to also have roles in autoimmune pathogenesis. 1 Our investigations of intestinal communities have shown that, unlike in healthy individuals, patients with systemic lupus erythematosus (SLE) commonly exhibit community-wide ecological microbiota instability. During high-disease activity, patients often have intestinal expansions (or blooms) of the anaerobic commensal, Ruminococcus (Mediterraneibacter) gnavus (RG), and this includes about a third of patients with lupus nephritis (LN). Pathogenic RG strains expressed a novel bacterial lipoglycan with conserved structural features (identified via mass spectroscopy). Gut leak of the lipoglycan into the immune system appears to induce high-level serum IgG2 antibodies concurrent with RG blooms and lupus flares.2 3 To investigate the effect on the immune system, we compared bulk RNAseq libraries, made from whole blood collected at time of disease flares. LN patients with RG blooms had significant overexpression of platelet and neutrophil activation transcripts, while the other LN patients had predominant B-cell activation and immune complex-mediated pathways, and interferon induced pathways.4 We repurposed the commercial proteomics assay system used in NIH AMP-sponsored high-dimensional discovery studies of self-proteins aimed at identifying WHO class and glomerular lesion activity via urine ‘liquid biopsy.’5 Multiplex subarrays were custom-designed to detect 30 human proteins implicated in platelet-associated thrombo-inflammation and neutrophil extracellular TRAPs/NETosis, and some in other immune pathways. Hybridization of urine from LN patients with RG blooms and high serum anti-lipoglycan antibodies, revealed elevated urine levels of proteins released from platelets, neutrophils, and endothelial cells, which were not detected in other patients with LN. In vivo murine challenge studies reiterated these findings.These data support the hypothesis that during blooms of the R. gnavus pathobiont, platelet and neutrophil-related pathways contribute to LN in a subset of patients. We postulate these patients are affected by a previously unrecognized endotype of LN in which exposure to the RG lipoglycan contributes to renal injury through pathways of thrombo-inflammation. This may be especially important as, despite the best therapy, within 15 years ~20% of LN patients progress to renal failure.6 Further characterization of this LN endotype linked to the gut microbiome may suggest less toxic therapeutic interventions then the glucocorticoids and immunosuppressants commonly used to treat LN.Learning Objectives At the end of this presentation participants will be able to:Discuss the potential roles of the gut microbiome and increased intestinal permeability in lupus pathogenesisExplain that intestinal expansions of candidate pathobionts occur commonly in SLEDescribe evidence that pathogenic strains of a keystone gut bacterial species can trigger a pathological cascade resulting in thrombo-inflammation pathways, which are also associated with worse outcomes in patients with sepsisReferences Silverman GJ, Azzouz DF, Gisch N, et al. The gut microbiome in systemic lupus erythematosus: Lessons from rheumatic fever. Nat Rev Rheumatol. 2024;20(3):143–57. doi: 10.1038/s41584-023-01071-8Azzouz D, Omarbekova A, Heguy A, et al. Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal. Ann Rheum Dis. 2019;78(7):947–56. doi: 10.1136/annrheumdis-2018-214856Azzouz D, Chen Z, Izmirly PM, et al. Longitudinal gut microbiome analyses and blooms of pathogenic strains during lupus disease flares. Ann Rheum Dis. 2023;82(10):1315–27. doi: 10.1136/ard-2023-223929Amarnani A, Rivera CF, Cornwell M, et al. Pathogenic strains of a gut commensal drive systemic platelet activation and thromboinflammation in lupus nephritis. bioRxiv. 2025. doi: 10.1101/2025.06.20.641288Fava A, Buyon J, Magder L, et al. Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis. JCI Insight. 2024;9(2). doi: 10.1172/jci.insight.172569Tektonidou MG, Dasgupta A, Ward MM. Risk of end-stage renal disease in patients with lupus nephritis, 1971–2015: a systematic review and bayesian meta-analysis. Arthritis Rheumatol. 2016;68(6):1432–41. doi: 10.1002/art.39594",
  "authors": [
    {
      "affiliations": [
        "Division of Rheumatology, NYU Grossman School of Medicine, New York, New York, USA"
      ],
      "name": "Gregg J Silverman"
    }
  ],
  "title": "08 New insights into the gut microbiome and lupus pathogenesis",
  "uid": "946f91ca-3b8c-5378-bc37-c13e4f9f8a8f"
}