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Zonulin Replaces "Sugar Challenge" Testing
in the Assessment of Intestinal Permeability

Recent research has revealed a pathway by which zonulin induces the breakdown of the normally tight junctions between gastrointestinal (GI) epithelial cells. The sophisticated research has led to the development of a superior test for the assessment of intestinal permeability of the upper bowel. The serum zonulin test directly determines the circulating levels of zonulin (antigen) that instigates a cascade of events resulting in large gaps between enterocytes. Such gaps permit the unregulated influx of macromolecules from the gut lumen. This permeability can elicit exacerbated immune and inflammatory responses that can result in conditions from food sensitivities (e.g. non-celiac gluten sensitivity) to serious auto-immune diseases. The zonulin test supplants the now-dated lactulose/mannitol "sugar challenge" (L/M) test.

(Image courtesy of ALPCO)
In research settings the "gold standard" test for abnormal permeability of epithelial cells (gut, heart, lungs, brain), is the Transepithelial Electrical Resistance (TEER) test using isolated cell systems. Although not clinically applicable for patients, the TEER test has been used as a gauge to assess the specificity of other tests such as the L/M and zonulin test. These two tests have been shown to correlate with the results of the complex TEER test. However, the L/M test, due to the very small size of the non-absorbable synthetic disaccharide lactulose (molecular weight=342), has an important limitation when compared to zonulin. The L/M does not permit definitive conclusions with respect to the potential for influx of much larger macromolecules such as protein fragments, lipopolysaccharide endotoxins or bacterial enterotoxins and proteases, and intact microbial cells. Therein lies the superiority of the zonulin test - it is associated with increased large gaps between the epithelial cells sufficient to permit influx of immune activating macromolecules.
The L/M test also suffers from some pre-analytical problems that do not affect the serum zonulin test. Lactulose is a common food additive and mannitol is a commonly used artificial sweetener. If patients consume foods that contain lactulose and/or mannitol despite instructions to the contrary, the test results can be confounded. Also, not all patients presenting with significant gastrointestinal symptoms are willing to consume the "sugar" test drink; lactulose is fermented in the colon which produces acetate, lactate and methane that can be associated with abdominal bloating/cramping, flatulence, and in rare cases vomiting. Further, patient noncompliance with complete urine collection and the inaccurate reporting of urine volume often results in artefactual results. The serum zonulin test avoids all of those issues and provides more accurate and specific information with respect to abnormal permeability of very significant macromolecules.

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Want to see the latest research on this topic?

Leffler DA, Kelly CP, Green PHR, et al. Larazotide Acetate for Persistent Symptoms of Celiac Disease Despite a Gluten-Free Diet: A Randomized Controlled Trial. Gastroenterology. 2015 June; 148(7):1311-1319
Ulluwishewa D, Anderson RC, McNabb WC, et al. Regulation of Tight Junction Permeability by Intestinal Bacteria and Dietary Components. J. Nutr. 141: 769–776, 2011.
Lerner A, Matthias T, Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease. Autoimmunity Reviews. 14 (2015) 479–489

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