Background/Purpose: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease in which lupus nephritis (LN) remains a major cause of morbidity and mortality. Zonulin, a modulator of intestinal permeability via tight junction regulation, has been implicated in the pathogenesis of several inflammatory diseases. Elevated zonulin levels are associated with systemic inflammation and have been linked to gut-organ axes, such as the gut-joint axis in spondyloarthritis and the gut-brain axis in neuropsychiatric disorders. However, its role in SLE and renal involvement remains largely unexplored. This study aimed to investigate the potential role of zonulin in SLE pathogenesis, with a specific focus on its association with LN.

Methods: Serum zonulin levels were measured in 46 patients with SLE (2019 ACR/EULAR criteria) and 41 healthy controls using an enzyme-linked immunosorbent assay (ELISA) in a cross-sectional study. Comprehensive demographic, clinical, laboratory, and clinimetric data were collected. Associations between zonulin levels and renal involvement, urinary sediment, serum creatinine, and urinary protein were analyzed. Zonulin expression in LN kidney biopsies was assessed by immunohistochemistry and immunofluorescence.

Results: Analysis of serum zonulin levels revealed a significant increase in SLE patients compared to healthy controls (mean 217.37 ± 56.96 vs. 120.63 ± 83.37; p < 0.0001). To determine whether zonulin levels differ between SLE patients with and without lupus nephritis (LN), we analyzed serum zonulin levels according to renal involvement. Interestingly, a substantial increase in zonulin levels was observed in patients with LN compared to those without LN (mean 244.19 ± 44.61 vs. 175.6 ± 48.67; p < 0.0001). To investigate whether serum zonulin levels might be associated with renal disease activity or damage, we analyzed zonulin levels in relation to urinary sediment abnormalities, serum creatinine levels, and urinary protein levels. Zonulin levels were significantly higher in patients with abnormal urinary sediment compared to those with normal sediment (mean 289.8 ± 50.25 vs. 202.1 ± 45.6; p < 0.0001). Additionally, serum zonulin levels showed a positive correlation with serum creatinine levels (p < 0.005; r = 0.16) and urinary protein levels (p < 0.0001; r = 0.349) (Fig. 1). IHC staining revealed local presence of zonulin in glomeruli and tubules, with higher expression in the latter, suggesting either local production or binding of circulating zonulin, and supporting a direct role in modulating glomerular and tubular function.

Conclusion: Elevated circulating zonulin is associated with renal involvement in SLE, suggesting a previously unexplored gut-kidney axis and a novel biological function of zonulin in regulating glomerular permeability.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/serum-zonulin-as-a-biomarker-of-renal-involvement-in-systemic-lupus-erythematosus-shedding-light-on-the-gut-kidney-axis/