Intestinal epithelial barrier disfunction in patients with chronic intestinal pseudo-obstruction

Background: Chronic intestinal pseudo-obstruction (CIPO) is a rare condition characterized by gastrointestinal (GI) impairment that is so severe to cause a clinical picture suggestive of a mechanical obstruction in the absence of any occlusion. Although degenerative or inflammatory neuro-interstitial cells of Cajal (ICC)-muscular abnormalities are the main pathogenetic mechanisms underlying gut dysfunction, other factors, i.e. intestinal epithelial barrier (IEB) abnormalities, may represent the initial insult contributing to symptoms and clinical manifestations. Aim: To assess the expression of occludin and zonula occludens-1 (ZO-1), two major components of tight junctions (TJs), as markers of IEB integrity in patients with CIPO. Methods: A number of n=26 clinically and histopathologically well characterized CIPO pts (15 F; age range: 16 - 75 yrs) were studied. CIPO cases were subdivided according to the histopathological analysis (IHC) in 3 groups: A) apparently normal n=7; B) inflamed n=8; C) degenerative n=10. Patients (n=8; 3 F, age range: 48 - 73 yrs) undergoing elective surgery for uncomplicated neoplastic diseases served as controls. CIPO and control jejunal full thickness biopsies were processed to assess occludin and ZO-1 mRNA and protein expression using q-PCR and WB. Results: Compared to controls, total occludin protein showed a marked decrease in CIPO pts (P<0.05); also, a tendency to a decreased occludin mRNA expression was found in CIPO vs. controls. Moreover, occludin oligomers, an index of occludin assembly in rafts TJs, were detected only in 19% of CIPO pts while all controls showed normal oligomerization. ZO-1 protein and mRNA expression did not change in CIPO vs controls. Interestingly, the tree histologically identified groups of CIPO showed a selective reduction of only one of the two analyzed components. Specifically, in group A and B occludin expression decreased, while in group C only ZO-1 content decreased. Conclusions: IEB integrity was altered in patients with CIPO as identified by the reduction of at least one of the TJ components. Moreover, the abnormal occludin oligomerization is indicative of TJ dysfunction, which increases the possibility of noxious agents passing through the intestinal wall in these patients. A better knowledge of IEB altered molecular mechanisms is expected to be translated in targeted therapeutic interventions.