Lipoglycan in Pathogenic Gut Microbe May Drive Lupus Nephritis

In a study in the Annals of the Rheumatic Diseases, NYU Langone Health researchers discovered that a significant immune response to a unique bacterial lipoglycan—including elevated serum antibody production—may drive lupus nephritis (LN) and offer a reliable biomarker for the inflammation underlying renal flares. LN affects roughly half of all patients with systemic lupus erythematosus (SLE) and is a major contributor to morbidity and mortality in this autoimmune disease.

Led by immunologist Gregg Silverman, MD, the Mamdouha S. Bobst Professor of Internal Medicine, with Abhimanyu Amarnani, MD, PhD, a fellow in the Division of Rheumatology, as first author, the study suggests that targeting the bacterial lipoglycan—or its immune cell binding partner, the pro-inflammatory receptor Toll-like receptor 2 (TLR2)—could offer a therapeutic alternative for some patients with LN. “Our findings set the stage for using selective antibiotics to block these bacterial growths, or using other inhibitory drugs to block the Toll-like receptor 2-mediated response triggered by these blooms,” Dr. Silverman says.

The new research is an extension of a 2019 study from Dr. Silverman and colleagues that found that specific strains of the commensal gut microbe Ruminococcus gnavus (recently renamed Mediterraneibacter gnavus) are more prevalent in a subset of patients with LN during disease flares. The association has held up across multiple studies of ethnically diverse SLE cohorts, but the underlying mechanism has remained unclear.

A subsequent 2023 study from the team also linked intestinal blooms of R. gnavus to higher SLE disease activity and showed that strains isolated from female patients with active LN produce a novel lipoglycan that attaches to the bacterial cell membrane.

The new study has sharpened the focus on that lipoglycan as a key target for disease detection and intervention. “Our study provides the foundational evidence that detection of anti-lipoglycan antibodies from Ruminococcus gnavus blooms in the gut could identify those people at increased risk of lupus nephritis,” says Dr. Silverman.

A Distinct LN Patient Subset

For a longitudinal study of female patients with SLE, the researchers recruited eight patients without and eight patients with LN, along with eight healthy controls. Four of the patients with SLE and LN had significant R. gnavus intestinal blooms; all four showed systemic inflammation and a robust antibody response against the bacterial lipoglycan, suggesting that they represented a new LN disease subtype.

The remaining four patients with LN but without significant R. gnavus blooms were more comparable to the healthy controls in both their R. gnavus gut populations and anti-lipoglycan antibody levels. The researchers observed similar results in a separate validation cohort of 20 patients with SLE and LN.

From additional experiments in mouse models of LN, Dr. Silverman and colleagues found that exposing the mice to either R. gnavus or to the R. gnavus lipoglycan triggered an immune response and serious renal damage resembling the damage observed in humans with LN. Blocking TLR2, the immune receptor activated by the R. gnavus lipoglycan, effectively prevented lupus-associated inflammation, showing that the in vivo responses to the lipoglycan toxin are TLR2-dependent.

Potential Therapeutic Alternative

“Our research reshapes the fundamental understanding of lupus nephritis, supporting our hypothesis that gut microbiome imbalances drive the disease, leading to Ruminococcus gnavus growths, which in turn produce the immune reactions and inflammation tied to long-term renal damage,” Dr. Silverman says. “These results lay the groundwork for demonstrating how clinicians could diagnose and potentially treat lupus nephritis earlier and more effectively.”

A planned clinical trial by Dr. Silverman’s team will test whether antibodies mounted against R. gnavus lipoglycan can serve as LN biomarkers, with the goal of stratifying patients based on their risk of a disease flare induced by gut dysbiosis.

Additional proposed clinical trials will test whether antibody-based approaches or TLR2 blockers can prevent or suppress LN flares, potentially offering much-needed alternatives to the current standard of immunosuppressants.