M1683 Increased Macromolecular Permeability in Non-Inflamed Colon of Ulcerative Colitis Involves Muscarinic Receptor Signalling Via Subepithelial Eosinophils

Abstract

Background and aim: Increased intestinal permeability has been shown in patients with UC In animal studies and studies in human volunteers, uptake of protein antigens can be regulated by cholinergic signalling pathways, eosinophils and mast cells. Our aim was to elucidate macromolecular permeability and ion secretion in macroscopically non-inflamed colon in UC. Materials and methods: Biopsies from fifteen UC patients in remission and fifteen healthy volunteers were studied in Ussing chambers for macromolecular permeability (horseradish peroxidase, HRP, 51Cr-EDTA), and electrophysiology during modulation of muscarinic receptors and mast cell stabilizer. The biopsies were examined by electron and light microscopy for eosinophils and mast cells in relation to cholinergic receptor localization. Results: Permeability to HRP was increased in UC patients (2.28 ± 0.20 pmol/cm2/h) compared to controls (0.99 ± 0.19). The elevated level of HRP uptake in UC was normalized by pretreatment with atropine (0.76 ± 0.26)or the mast cell stabilizer lodoxamide tromethamine (1.16 ± 0.28). Immunohistochemistry showed increased numbers of lamina propria eosinophils expressing muscarinic receptor subtypes M2 and M3 in the UC group, whereas mast cells did not express muscarinic receptors. Electron microscopy showed signs of activation (degranulation) of eosinophils and mast cells upon exposure to the acteylcholine analogue, carbachol. Conclusions: Increased transmucosal uptake of protein antigens in the non-inflamed colon of UC involves cholinergic signalling and activation of mast cells. Subepithelial eosinophils expressing muscarinic receptors may be involved in regulating this process.