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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

In coeliac disease, there is an increase in passive intestinal permeability to large polar molecules, ranging in size from proteins' down to oligosaccharides. In contrast, small polar molecules are malabsorbed. We have described34 our preliminary findings using a test of intestinal permeability (known as the cellobiose/mannitol test or 'sugar test' for short), based on the simultaneous oral administration and five-hour urinary recoveries of two probe molecules. The larger molecule used was cellobiose, a disaccharide (molecular radius 5A), and the smaller was mannitol, a polyhydric alcohol (molecular radius 4A). We showed that untreated coeliacs absorbed significantly more cellobiose, and less mannitol than control patients, and, when the result was expressed as a ratio (cellobiose recovery/ mannitol recovery), the discrimination was greatly enhanced. We postulated that, by expressing the result in this way, the sensitivity of the test as a screening procedure would be increased, and that, providing the two molecules were not too dissimilar