The aspirin augmented standardized lactulose mannitol test as a measure of the 'health' of the gastrointestinal tract : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Massey University, Palmerston North, New Zealand

Abstract

In this thesis, I studied the ‘classical’ lactulose mannitol test for intestinal permeability that has been used to measure the integrity of the intestinal mucosa and thus to provide an index of recovery from inflammatory bowel disease (IBD) and from autoimmune diseases such as coeliac disease. Perusal of the literature indicates that the protocol for the test has not been standardized and a variety of different test protocols have been used. Hence there are differences in the duration of urinary sampling, the doses of the two test probes, the volumes of fluid consumed during the test and the administration of the test during the fasted or fed state. There is therefore a need for a standardized test. The bulk of the research conducted in this thesis was to develop an optimal protocol with a standardized osmolarity (720 osmol l-1) for the test solution that contained 10 g of lactulose and 5 g of mannitol dissolved in 100 ml of water. Similarly the total fluid intake was standardized to 700 ml. The volumes of fluid consumed over the experimental period were also standardized in order to control for any osmolar effects of the test drink and to hydrate the subjects sufficiently to enable them to produce half-hourly urine samples of a reasonable volume. The rates of excretion and the timings of the peaks in the excretion of mannitol and lactulose were found to vary over time in healthy subjects. Hence the rate of mannitol excretion peaked during the first two hrs whilst the rate of lactulose excretion peaked at four hrs. The correlation between urinary excretion with intestinal transit times were confirmed using a wireless motility capsule. The work with the wireless motility capsule indicated that the probe sugars were in the small intestine from 2½ - 4 hrs and in the proximal colon from 4½ - 6 hrs following dosage with the test solution. Hence a sample collected during the 2½ - 4 hr period is best for assessing permeability of the small intestinal mucosa in healthy subjects. The wireless motility capsule also confirmed that the standardized dose of the lactulose mannitol did not influence gastric transit time or that through the small intestine and large intestine. These findings confirmed that the standardized test was determining absorption during transit of the test sugars through the small and the large intestine. The effect of co-dosage with 600 mg of aspirin in the standardized test was then examined as a means of assessing the effect of a reproducible noxious stimulus on the absorption of the sugar probes. This agent augmented small intestinal permeability to lactulose and decreased its permeability to mannitol. Furthermore dosage with aspirin amplified the effect of a pre-existing adverse stimulus such as smoking. Hence the aspirin augmented test could conceivably be used to ‘unearth’ sub-clinical inflammation. Further work explored the effect of an antioxidant, ascorbic acid, on mucosal permeability. The results showed that, rather than mitigating the adverse effects of aspirin, ascorbic acid augmented intestinal permeability. In summary the work in this thesis has enabled the development of a standardized test that optimizes the ability of the lactulose mannitol test to detect clinical disorders of absorption. Further, augmenting the test with a single dose of aspirin may be useful as an index of gut health or robustness.