P007 Disruption of phosphatidylcholine paracellular movement to intestinal mucus predisposes to Ulcerative Colitis
W. Stremmel*1, S. Staffer1, M. Schneider2, H. Gan-Schreier1, A. Wannhoff1, H. Wolburg3, M. Bach4, T. Efferth2
1University Hospital of Heidelberg, Internal Medicine IV, Div. of Gastroenterology, Heidelberg, Germany, 2Johannes Gutenberg University, Institute of Pharmacy & Biochemistry, Mainz, Germany, 3University Hospital of Tübingen, Medicine, Tübingen, Germany, 4Kirchhoff Institute of Physics, Physics, Heidelberg, Germany
Phosphatidylcholine (PC) in intestinal mucus forms a hydrophobic barrier against colonic microbiota. Ulcerative colitis (UC) is a common inflammatory bowel disease characterized by bloody diarrhea and pain, with a defective mucosal barrier being the most likely underlying cause and for which symptomatic anti-inflammatory therapy is often unsuccessful. Here we propose that our observation of an intrinsic low mucus PC content is a key pathogenic feature of UC, which may result from the disruption of PC translocation into mucus.
The mechanism of luminal PC secretion was investigated in CaCo2 human intestinal tumor cells grown for 21 days in Transwell tissue culture dishes until apical/basolateral polarization and establishment of tight junctions (TJ. For functional in vivo studies genetic mouse models with ulcerative colitis were employed (intestinal deletion of kindlin 1 and 2). Biopsy samples of patients with UC, Crohn's disease and controls were examined in regard to luminal PC Transport.
This study demonstrates for the first time that phospholipids containing choline but no other head groups translocate by a novel paracellular transport pathway across lateral tight junctions (TJ) to the apical mucus compartment. This translocation is stimulated by apical bicarbonate secretion mediated by cystic fibrosis transmembrane conductance regulator. The apical accumulation of negative charge drives PCs from TJ to the mucus side where PC is trapped to membrane-localized mucin 3. This concept of PC transport across TJ was confirmed in mice with TJ defects caused by intestinal deletion of kindlin 1 and 2: luminal PC secretion in these mice was reduced by 70 %, with the consequent low mucus PC concentration producing an UC phenotype that was mitigated by oral PC supplementation. When biopsies of UC and Crohn's disease patients and normal controls were compared, a disturbed TJ barrier with expanded crypt diameters was detected and paracellular luminal PC movement was suppressed only in UC patients.
Thus, a low PC concentration resulting from disrupted paracellular PC translocation into mucus and the consequent loss of hydrophobic protection by intestinal mucosa is a pathogenic mechanism in the development of UC. Topical PC supplementation delivered by delayed-release oral PC preparations can re-establish the hydrophobic barrier and could serve as an innovative treatment for UC.