Zonulin, a protein that modulates intestinal permeability, is upregulated in several autoimmune diseases and is involved in the pathogenesis of autoimmune diabetes in the BB/Wor animal model of the disease. To verify the association between serum zonulin levels and in vivo intestinal permeability in patients with type 1 diabetes, both parameters were investigated in different stages of the autoimmune process. Forty-two percent (141 of 339) of the patients had abnormal serum zonulin levels, as compared with age-matched control subjects. The increased zonulin levels correlated with increased intestinal permeability in vivo and changes in claudin-1, claudin-2, and myosin IXB genes expression, while no changes were detected in ZO1 and occludin genes expression. When tested in serum samples collected during the pre-type 1 diabetes phase, elevated serum zonulin was detected in 70% of subjects and preceded by 3.5 ؎ 0.9 years the onset of the disease in those patients who went on to develop type 1 diabetes. Combined, these results suggest that zonulin upregulation is associated with increased intestinal permeability in a subgroup of type 1 diabetic patients. Zonulin upregulation seems to precede the onset of the disease, providing a possible link between increased intestinal permeability, environmental exposure to non-self antigens, and the development of autoimmunity in genetically susceptible individuals.

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A not previously reported increase of intestinal permeability to mannitol, clear-cut and not associated with that of the larger probe, is found in type I uncomplicated diabetes mellitus. These results may describe a primary feature of type I diabetes mellitus and the initial steps of evolution to celiac disease.

Malnutrition and absence of exogenous luminal nutrients in the gastrointestinal tract affect intestinal permeability (IP) leading to an increased penetration of substances that passively cross intestinal epithelium via intercellular pathways. We hypothesised that an increase in IP could occur in patients with anorexia nervosa because of their prolonged fasting and chronic malnutrition. Therefore, we assessed IP in 14 drug-free anorexic women and 19 drug-free agematched healthy women by means of the lactulose/mannitol (LA/MA) test. To this purpose, after an overnight fast, subjects ingested an oral solution containing 5 g lactulose and 2 g mannitol in 100 ml water. Urine specimens were collected immediately before and 30, 60, 120, 180, 240 and 300 min after the ingestion of the sugar solution. Urinary lactulose and mannitol were determined by high-performance anion exchange chromatography coupled with pulsed amperometric detection. We found that IP, as expressed by the 5-h LA/MA excretion ratio, was significantly decreased in anorexic women because of a lower urinary recovery of lactulose. Moreover, in patients, the time course of lactulose excretion significantly differs from healthy controls. These results do not confirm our hypothesis of increased IP in anorexia nervosa. Since IP reflects the anatomo-functional status of intestinal mucosa, the present findings support the idea that changes in the anatomo-physiology of intestinal mucosa occur in anorexia nervosa.

5-Fluorouracil (5-FU), in association with leucovorin (LV), is the most used chemotherapy agent in the treatment of colorectal cancer. Response rate, as well as side-effect incidence, increases with the dose intensity of regimens that are used. The most common dose-limiting toxicity for 5-FU/LV modulation is diarrhea. To assess the modification of small intestinal function, we investigated the changes in intestinal permeability (IP) and intestinal absorption (IA) in 41 chemo-naive patients (21 men and 22 women; mean age, 61 +/- 9 years) with advanced colorectal cancer after treatment with the association of folinic acid and 5-FU. After chemotherapy administration, we found a marked increase in IP and a reduction in IA, measured as cellobiose-mannitol (CE-MA) ratio (p < 0.0001) and D-xylose absorption (p = 0.0001), respectively. Patients who experienced diarrhea have an increase in CE-MA ratio and a reduction in D-xylose absorption values, both statistically significant. Cellobiose-mannitol ratio and D-xylose absorption tests can be used for the assessment of toxic effect of 5-FU on mature intestinal epithelium and also for evaluating the role of cytoprotective agents.