The Role of Endometriosis in Intestinal Inflammation: A Combined Mendelian Randomization and Cellular Study

Abstract

This study aims to assess whether endometriosis causally increases the risk of IBD through Mendelian randomisation (MR) analysis and to elucidate potential mechanisms using in vitro experiments. A two-sample Mendelian randomisation (MR) analysis was conducted using genome-wide association study datasets for endometriosis and IBD, including ulcerative colitis and Crohn's disease. Causal inference was assessed using inverse variance weighting, MR-Egger, and weighted median methods, with MR-PRESSO used to detect horizontal pleiotropy. Additionally, peritoneal fluid from endometriosis patients (EM-PF) and healthy controls (CN-PF) was used to treat Caco-2 cells. Cell viability, apoptosis, barrier function, and inflammatory cytokine expression were analysed using MTT, TUNEL, transepithelial electrical resistance (TEER), Western blot, and qRT-PCR assays. MR analysis identified a significant causal association between endometriosis and IBD risk (IVW: β = 0.15–0.47, p < 0.05). Sensitivity analyses confirmed result robustness with minimal pleiotropy and heterogeneity. Experimental results showed that EM-PF significantly reduced Caco-2 cell viability and TEER values while increasing apoptosis and epithelial permeability (p < 0.01). Western blot and immunofluorescence staining revealed a marked decrease in tight junction proteins (ZO-1, Occludin) and an upregulation of inflammatory cytokines (IL-6, IL-8, IL-1β) in the EM-PF group (p < 0.01). Our findings provide genetic and experimental evidence supporting a causal role of endometriosis in increasing IBD risk. Endometriosis-associated peritoneal fluid may contribute to gut inflammation and epithelial dysfunction, offering new insights into the pathophysiological connection between these conditions.