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

Mckenna M Bowes; Desiré Casares-Marfil; Amr H Sawalha

doi:10.1016/j.clim.2024.110173

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

Clin Immunol. 2024 May:262:110173. doi: 10.1016/j.clim.2024.110173. Epub 2024 Mar 8.

Authors

Mckenna M Bowes¹, Desiré Casares-Marfil², Amr H Sawalha³

Affiliations

¹ Division of Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
² Division of Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: DEC139@pitt.edu.
³ Division of Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA; Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Lupus Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: asawalha@pitt.edu.

PMID: 38460891
PMCID: PMC11009052 (available on 2025-05-01)
DOI: 10.1016/j.clim.2024.110173

Abstract

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 × 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 × 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.

Keywords: DNA methylation; Epigenetics; Intestinal permeability; Lupus; Zonulin.

MeSH terms

Case-Control Studies
DNA Methylation*
Epigenesis, Genetic
Female
Humans
Intestinal Barrier Function
Lupus Erythematosus, Systemic* / genetics

Grants and funding

R01 AI097134/AI/NIAID NIH HHS/United States