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TOPLINE:

Researchers identified a distinct lupus nephritis (LN) endotype characterized by the intestinal expansion of the pathobiont Ruminococcus gnavus (RG) and release of a proinflammatory lipoglycan (LG) toxin. Patients with RG blooms had gene expression profiles indicating platelet activation and neutrophil degranulation. Murine experiments demonstrated that only RG strains producing the immunogenic LG toxin induced increases in megakaryocyte number, platelet activation, and renal injury.

METHODOLOGY:

• RG strains isolated from patients with active LN produce a novel form of LG — a complex glycan with a unique structure — recognized by spontaneously arising anti-LG antibodies found at high levels in approximately one third or more of patients with active LN. Researchers investigated mechanisms by which intestinal RG blooms affect autoimmune pathogenesis in patients with LN.
• They analyzed a pilot cohort of female patients with systemic lupus erythematosus either with LN as defined by clinical criteria (n = 8) or without renal disease (n = 8), dichotomized by the presence or absence of gut abundance of RG (> 1% defined as blooms). Those with intestinal RG blooms had higher serum levels of anti-LG immunoglobulin G antibody.
• A validation cohort from the control arm of the ACCESS trial included 20 patients with active biopsy-proven class III or IV LN from 11 of 21 clinical sites across the US, evaluated for blood transcriptomic profiles and anti-LG antibody levels with a cutoff of 59,000 U/mL.
• Murine studies involved wild-type mice and lupus-prone FcγRIIb^−/− mice colonized with RG strains isolated from patients with LN — either LG-producing or LG-nonproducing strains — via oral gavage after antibiotic pretreatment or injected intraperitoneally with purified LG preparation (1.5 μg/g), with outcomes assessed at 2 and 4 weeks post-gavage or 6 days post-injection.
• The outcome measures included whole-blood RNA sequencing for gene expression profiling, serum levels of platelet factor 4 (PF4) and neutrophil extracellular trap (NET) fragments (myeloperoxidase, citrullinated histone-3, and double-stranded DNA), flow cytometry for platelet P-selectin expression and megakaryocyte quantification, and renal histology for cellular infiltration and injury scoring (NETosis markers).

TAKEAWAY:

• In the pilot cohort, patients with LN and RG blooms exhibited higher expression of gene modules related to platelet activation and neutrophil migration, chemotaxis, and degranulation than patients with LN without blooms.
• In the validation cohort, anti-LG antibody-positive patients (n = 12) had significantly elevated platelet activation gene scores (P = .04) and serum PF4 protein levels (P = .02) compared with anti-LG antibody-negative patients (n = 8) and exhibited gene signatures of increased neutrophil degranulation. Anti-LG antibody levels directly correlated with platelet activation (coefficient of correlation [r], 0.47; P < .05) and NET fragmentation (r, 0.45; P < .05).
• Murine colonization with LG-producing RG strains induced significant renal cellular infiltration in FcγRIIb^−/− lupus-prone mice (P < .001), with increased numbers of splenic megakaryocytes compared with sham-gavaged controls.
• Intraperitoneal injection of LG preparation in wild-type and FcγRIIb^−/− lupus-prone mice significantly increased platelet P-selectin expression after ex vivo thrombin stimulation (P = .02 and P = .04, respectively) and numbers of splenic megakaryocytes at 6 days post-injection.

IN PRACTICE:

“Our study provides the foundational evidence that detection of antilipoglycan antibodies from Ruminococcus gnavus blooms in the gut could identify those people at increased risk of lupus nephritis,” said senior investigator and immunologist Gregg Silverman, MD, in a news release. 

SOURCE:

This study was led by Abhimanyu Amarnani, MD, PhD, NYU Grossman School of Medicine in New York City. It was published online on April 23, 2026, in Annals of the Rheumatic Diseases.

LIMITATIONS:

The cohort size in the pilot study was modest and was derived from a single site; it also comprised only female patients. Data on gut microbiota were unavailable for the validation cohort.

DISCLOSURES:

This study received funding in part from National Institutes of Health (NIH) grants, the Lupus Foundation of America Gilkeson Career Development Award, the Department of Defense CDMRP, and Sanofi. One author disclosed receiving financial support from Sanofi and the NIH, grant support from Novartis and Genentech, and reported having a patent pending to NYU.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.