Intestinal permeability correlates with disease activity and DNA methylation changes in lupus patients

Objective: Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease that can involve various organ systems. Several studies have suggested that increased intestinal permeability may play a role in the pathogenesis of lupus. The aim of this study was to elucidate the relationship between intestinal permeability, disease activity, and epigenetic changes in lupus patients. Methods: A total of 25 female lupus patients were included in this study. Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores were used as indicator of disease activity. Plasma zonulin levels were measured, using an ELISA, as a marker of intestinal permeability. Genome-wide DNA methylation patterns were assessed in neutrophils for 19 of the lupus patients using the Infinium MethylationEPIC array. Linear regression and Pearson's correlation were used to evaluate the correlation between zonulin concentrations and SLEDAI scores. The relationship between DNA methylation levels and zonulin concentrations was assessed using beta regression, linear regression, and Pearson's correlation, adjusting for age and race. Results: Intestinal permeability positively correlated with disease activity in lupus patients (p-value = 7.60 x 10-3, r = 0.53). DNA methylation levels in 926 CpG sites significantly correlated with intestinal permeability. The highest correlation was identified in LRIG1 (cg14159396, FDR-adjusted p-value = 1.35 x 10-12, adjusted r2 = 0.92), which plays a role in intestinal homeostasis. Gene Ontologies related to cell-cell adhesion were enriched among the genes that were hypomethylated with increased intestinal permeability in lupus. Conclusion: Our data suggest a correlation between increased intestinal permeability and disease activity in lupus patients. Further, increased intestinal permeability might be associated with epigenetic changes that could play a role in the pathogenesis of lupus.