Intestinal permeability in coeliac disease: the response to gluten withdrawal and single-dose gluten challenge.

Abstract

SUMMARY Intestinal permeability has been studied in 21 patients with coeliac disease in relapse and after gluten withdrawal using an oral test of intestinal permeability based on the simultaneous oral administration of two probe molecules. The increased absorption of the larger molecule (cellobiose) and the decreased absorption of the smaller (mannitol) found in untreated coeliac disease both returned to normal within five months of starting treatment, the abnormality in cellobiose absorption correcting more rapidly than that of mannitol. After exposure to a single oral dose of gluten, the intestinal permeability of six patients with treated coeliac disease became transiently abnormal with an increased absorption of cellobiose, returning to normal within one week. The possible structural and functional implications of these findings are discussed. The cellobiose/mannitol ratio appears to be of value in assessing the response to gluten withdrawal in coeliac disease, and also in monitoring patients who are already established on a gluten free diet by detecting dietary lapses and 'non-responding coeliac disease'. It may also offer an alternative to jejunal biopsy in patients subjected to gluten challenge.The abnormal intestinal permeability of untreated coeliac disease is characterised by a reduced absorption of small hydrophilic molecules' with a paradoxical increase in absorption of larger molecules.2 3 We have used the simultaneous oral administration of two water-soluble probe molecules, mannitol (molecular radius 04 nM) and cellobiose (molecular radius 0.5 nM) to demonstrate these changes, and have shown that patients with coeliac disease excrete more cellobiose and less mannitol in their urine than controls, after oral ingestion of these molecules in hypertonic solution.4 Expression of the result as a ratio of cellobiose recovery to mannitol recovery allows clear separation of normal subjects from coeliacs, a finding confirmed by others using a similar test system.5 The absorption of mannitol from the normal small bowel is 10-200 fold greater than that of cellobiose, suggesting, in the absence of active transport,36 that, while mannitol may be absorbed through classical transcellular aqueous pores, cellobiose is excluded by its size. The effective pore radius must, therefore, lie between 0.4 and 0-5 nM, in agreement with earlier estimates,7 8 and much smaller than the estimate of 0-8 nM by Fordtran et al,9

Role of Corticotropin-releasing Factor in Gastrointestinal Permeability

“…113 More precise in vitro investigations revealed that although strict gluten withdrawal restored intestinal histology, a subjacent defect in mucosal permeability, measured by cellobiose/mannitol ratio, was transiently induced by short exposure to gluten, suggesting that increased intestinal permeability in celiac disease could be a primary defect. 135 Recently, this defect in intestinal permeability has been related to altered expression of TJ genes related to permeability, polarity, and cell proliferation in active celiac disease, 136 partly through the activation of the zonulin pathway in a MyD88-dependent fashion. 137,138 Again, the majority of genes returned to normal after 2 years of gluten eviction with the exception of PPP2R3A, possibly indicating a constitutive defect in these patients.…”

Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats

“…These cells play a pivotal role in the maintenance of immune tolerance by down-regulating the immune response to foreign antigens when they gain access beyond the intestinal mucosal barrier (6). Recent studies in humans and in animal models have linked the presence of increased intestinal permeability to the occurrence of autoimmune diseases (8)(9)(10)(11)(12)(13). However, a causative role for the loss of the intestinal barrier function has not been definitively established.…”

Detection of Gluten Exorphin B4 and B5 in Human Blood by Liquid Chromatography-Mass Spectrometry/Mass Spectrometry

“…Here an ultrafiltration method followed by electrospray ionization (ESI) liquid chromatography-tandem mass spectrometry (LC-MS/MS) is used to determine if GEs can be detected in blood samples from subjects with compromised intestinal lining. Subjects with gluten-induced enteropathy (Celiac Disease, CD) were chosen as model subjects, because CD is well-known to result in increased intestinal permeability to macromolecules [6][7][8], and is frequently associated with mental disorders [9][10][11].…”