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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

SUMMARY The cellobiose/mannitol (Ce/Ma) test is a non-invasive technique for investigating intestinal permeability. In coeliac disease there is a decreased absorption of small molecules and paradoxically increased absorption of large molecules. The simultaneous administration of cellobiose and mannitol as two probe molecules allows the permeability of the small bowel mucosa to be studied, eliminating extraneous factors such as gastric emptying, and incomplete urine collection. One thousand and ten patients presenting to a gastroenterology clinic with symptoms, signs, or biochemical indices compatible with coeliac disease had a Ce/Ma test. Eight hundred and seventeen had a normal test and of these 197 had a jejunal biopsy showing 148 normal mucosa, two coeliac disease, 43 non-specific abnormalities, four giardiasis. One hundred and ninety three had an abnormal test; of these 132 had a jejunal biopsy showing 62 normal mucosa, 48 coeliac disease, and 22 other abnormalities. Considering those who had jejunal biopsies, the sensitivity of the test for coeliac disease is 96%, specificity 70%, the predictive value of the positive 36%, and predictive value of the negative 99%. Eleven per cent of the patients with a 'false positive' test had abnormalities in the jejunal biopsy or a diagnosis which could explain the abnormal permeability.The Ce/Ma test is a non-invasive investigation of small bowel permeability. l 2 Cellobiose, a disaccharide (molecular radius 0.50 nm) and mannitol, a polyhydric alcohol (molecular radius 0-40 nm) are taken orally in hypertonic solution and a five hour urine collection is analysed for both probe molecules, the results being expressed as a ratio of the percentage recoveries.' In coeliac disease more cellobiose and less mannitol is absorbed than in normal subjects.' By expressing the results as a ratio there is good separation of coeliacs from normal subjects and the influence of certain non-intestinal factors acting similarly on both molecules such as renal impairment, gastric and bladder emptying and are eliminated.4Although results of the Ce/Ma test have been reported previously they relate to small numbers of