Evaluation of polysucrose 15000 as a marker of intestinal permeability

Abstract: Evaluation of Polysucrose 15000 as a marker of intestinal permeability Hans Öman, Department of Laboratory Medicine, Division of Clinical Immunology and Transfusion Medicine, Karolinska Hospital, 171 76 STOCKHOLM, SWEDEN. Polysucrose (PS) is a synthetic copolymer of sucrose and epichlorohydrin, which can beproduced in a variety of molecular sizes. The aim of the study was to evaluate thefunctionality of PS 15000, mean mol wt 14700, as a marker for intestinal permeability tomacromolecules. In human tests, PS 15000, sometimes together with 51Cr-labelledethylenediaminetetraacetic acid (EDTA) and 14C-mannitol, was given orally and the renallyexcreted portion of the markers was quantified.An enzyme immunoassay for PS 15000 was developed for the measuring of PS excretion inurine. PS was shown to be fairly resistant to bacterial degradation. Intravenous injection of PS15000 revealed rapid renal clearance. Oral PS 15000 challenge in healthy volunteers gave thehighest excretion values in the 0-4 h sample followed by a gradual decline, the total excretionbeing about 0.02% over 12 hours.Rheumatoid arthritis (RA) patients on non-steroidal anti-inflammatory drug (NSAID)treatment had a twofold increased PS 15000 excretion; initially untreated RA patients withnormal PS 15000 test rose in excretion values after one week of NSAID treatment, indicatingincreased intestinal permeability as a consequence of the treatment rather than being an RAattribute.Patients with Crohn's disease had a significantly increased PS 15000 excretion for theintervals 4-8 h and 8-12 h; permeability was more increased in small-intestinal than in colonicdisease, and more increased in active than in quiescent disease.In healthy controls7 tested on four occasions, PS 15000 was compared to the paracellularmarker 5ICr-EDTA and to the transcellular marker 14C-mannitol under different testconditions. PS 15000 excretion values were strongly correlated to those of 5ICr-EDTA, withno correlation to those of 14C-mannitol. PS 15000 and 51Cr-EDTA were not affected by ahyperosmolar test solution but showed increased excretion after one week of NSAIDpretreatment, whereas 14C-mannitol excretion was markedly reduced by the hyperosmolar testsolution but was not affected by NSAID pretreatment.In a continued study on the healthy controls a standardised liquid meal increased the numberof time intervals with a significant NSAID-induced change in excretion for both PS 15000and 51Cr-EDTA, i.e., tended to improve the disease vs. health discrimination ability of thetests. Calculation of paracellular/transcellular excretion ratios was not beneficial.Finally, tight junction function or endocytosis were modulated in rat ileal mucosa mounted inUssing chambers and the effect on the permeability to PS 15000 and 51Cr-EDTA wasevaluated. Modulation affected both markers in a similar way, indicating that PS 15000,despite its size, behaves as a marker of paracellular intestinal permeability.PS 15000 seems to fulfil many criteria for an ideal marker of paracellular intestinalpermeability.Key words Polysucrose; Permeability; Intestinal Absorption; Cell Memhrane Permeahility; Molecular Weight;Macromolecular systems; Biological Markers; Biological Transport; Crohn Disease; Arthritis, Rheumatoid;Anti-lnflammatory Agents, Non-Steroidal; Chromium Radioisotopes; EDTA; Mannitol; Intestine, Small;Intestinal Mucosa; Mucous Membrane; Intercellular Junctions; EndocytosisStockholm 1996 The thesis is written in English ISBN 91-628-2074-5