Serum zonulin measured by enzyme-linked immunosorbent assay may not be a reliable marker of small intestinal permeability in healthy adults

Tatucu-Babet, Oana A.; Forsyth, Adrienne; Owen, E.; Navarro-Perez, Diana; Radcliffe, Jessica; Benheim, Devin; Mendis, Himasha; Jois, Markandeya; Itsiopoulos, Catherine; Tierney, Audrey C.

doi:10.1016/j.nutres.2020.05.003

Cited by 15 publications

(8 citation statements)

References 39 publications

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“…Zonulin related proteins are the fecal proteins that reflect intestinal permeability, and their increased fecal levels are considered to be a marker of an impaired intestinal barrier, especially in the small intestine [12]. Increased serum/plasma ZRP concentrations have been found in different immunopathological diseases, such as food allergies, infections of the gastrointestinal tract, systemic autoimmune diseases, and inflammatory diseases of the intestine [13]. There are discrepancies in the correlation between fecal and serum ZRP levels [14].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Fecal Zonulin as a Noninvasive Biomarker of Intestinal Permeability in Pediatric Patients with Inflammatory Bowel Diseases—Correlation with Disease Activity and Fecal Calprotectin

Szymańska

Wierzbicka

Dądalski

et al. 2021

JCM

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Background: Recent data indicate that increased intestinal permeability plays a key role in the pathogenesis of inflammatory bowel diseases (IBD) and correlates with disease flare. Since zonulin related proteins (ZRP) are the proteins that increase permeability in the epithelial layer of the small intestine by reversibly modulating the intercellular tight junctions, they may serve as a new, noninvasive biomarker of disease activity. The aim of this study was to investigate fecal ZRP in pediatric IBD patients as well as its correlation with disease activity and fecal calprotectin (FCP). Methods: Ninety-four individuals: 47 Crohn’s disease (CD) patients, 41 ulcerative colitis (UC) patients, and 6 healthy controls were examined for fecal ZRP. Values were correlated to IBD type, disease activity for IBD patients, and FCP for all children included in the study. A stool specimen was collected the day before the visit to the hospital, then fecal ZRP and FCP were tested using the ELISA test. Non-parametric statistical tests were used for data analysis. Results: The level of fecal ZRP was higher among IBD patients compared to the control group (CG): medians for CD—113.3 (53.6–593.6) ng/mL; UC—103.6 (50.7–418.3) ng/mL; and CG—46.9 (31.8–123.0) ng/mL (p < 0.05). No difference in fecal ZRP concentration was observed between children with CD and those with UC (p = 0.55). A slight correlation between disease activity (PCDAI for CD and PUCAI for UC) and the fecal ZRP level was found for CD (p = 0.03/R = 0.33), but not UC (p = 0.62/R = 0.08), patients. A correlation between fecal ZRP and FCP was observed (R = 0.73, p = 0.00). Conclusions: Fecal ZRP levels are increased among those with IBD, are associated with CD activity, and strongly correlate with FCP. Further research into the role of intestinal permeability in IBD and the clinical usefulness of ZRP in IBD is warranted.

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Section: Discussionmentioning

confidence: 99%

“…The ZRP results were given in ng/mL. Based on the manufacturer's declaration, the intra-assay and inter-assay coefficients of variation were 3.4% and 13.3%, respectively [13]. The same method (the ELIZA test) was used to assess FCP levels, and values were given in µg/g.…”

Section: Fecal Samplesmentioning

confidence: 99%

Fecal Zonulin as a Noninvasive Biomarker of Intestinal Permeability in Pediatric Patients with Inflammatory Bowel Diseases—Correlation with Disease Activity and Fecal Calprotectin

Szymańska

Wierzbicka

Dądalski

et al. 2021

JCM

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“…Several additional nutrients and nutraceuticals have been investigated for their effects on exercise-induced changes in GI barrier integrity. Supplementation with vitamin C (1 g) two hours before exercise was found to reduce exercise-induced increases in plasma lipopolysaccharide 49 , a marker of endotoxemia that correlates with GI barrier permeability 50 . Likewise, 14 days of zinc carnosine supplementation (37.5 mg, twice daily) reduced post-exercise intestinal permeability by 71% in comparison to placebo, possibly through the enhancement of tight junction formation and stability 44 .…”

Section: Supplements Purported To Enhance Gut Function With Exercisementioning

confidence: 98%

Sport Supplements and the Athlete’s Gut: A Review

Wilson

2021

Int J Sports Med

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Vigorous or prolonged exercise poses a challenge to gastrointestinal system functioning and is associated with digestive symptoms. This narrative review addresses 1) the potential of dietary supplements to enhance gut function and reduce exercise-associated gastrointestinal symptoms and 2) strategies for reducing gastrointestinal-related side effects resulting from popular sports supplements. Several supplements, including probiotics, glutamine, and bovine colostrum, have been shown to reduce markers of gastrointestinal damage and permeability with exercise. Yet, the clinical ramifications of these findings are uncertain, as improvements in symptoms have not been consistently observed. Among these supplements, probiotics modestly reduced exercise-associated gastrointestinal symptoms in a few studies, suggesting they are the most evidenced-based choice for athletes looking to manage such symptoms through supplementation. Carbohydrate, caffeine, and sodium bicarbonate are evidence-based supplements that can trigger gastrointestinal symptoms. Using glucose-fructose mixtures is beneficial when carbohydrate ingestion is high (>50 g/h) during exercise, and undertaking multiple gut training sessions prior to competition may also be helpful. Approaches for preventing caffeine-induced gastrointestinal disturbances include using low-to-moderate doses (<500 mg) and avoiding/minimizing exacerbating factors (stress, anxiety, other stimulants, fasting). Adverse gastrointestinal effects of sodium bicarbonate can be avoided by using enteric-coated formulations, low doses (0.2 g/kg), or multi-day loading protocols.

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“…Almost all the studies measuring zonulin have utilized commercially available ELISAs, as opposed to the in-house assays exclusively used by the researchers who discovered zonulin ( Wang et al, 2000 ). The identity of zonulin quantified by different assays and its correlation to functional intestinal permeability tests, such as the lactulose-mannitol test, have been extensively debated recently ( Scheffler et al, 2018 ; Ajamian et al, 2019 ; Tatucu-Babet et al, 2020 ; Fasano, 2021 ; Massier et al, 2021 ; Power et al, 2021 ; Seethaler et al, 2021 ; Sollid and Koning, 2021 ). To reconcile the discrepancies, it was proposed that the commercially available zonulin ELISAs recognize other proteins that are structurally and functionally related to the zonulin protein originally described by Dr. Alessio Fasano ( Wang et al, 2000 ), termed zonulin family peptides (ZFPs; Fasano, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

In vitro Effects of Bacterial Exposure on Secretion of Zonulin Family Peptides and Their Detection in Human Tissue Samples

et al. 2022

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Commercially available ELISAs for zonulin (pre-haptoglobin 2), a protein with tight junction regulatory activity in the epithelia, were recently shown to recognize other proteins that are structurally and functionally related to zonulin, termed zonulin family peptides (ZFPs). With little or no information about the identity and property of ZFPs, various commercial zonulin ELISA kits are widely utilized in research as a marker of intestinal permeability. Bacterial exposure is a known trigger for the secretion of zonulin, but it remains unclear whether distinct bacteria differ in their capability to stimulate zonulin secretion. We hypothesized that ZFPs are similar to zonulin regarding response to bacterial exposure and aimed to compare the effects of non-pathogenic, Gram-negative bacteria (Escherichia coli RY13 and E. coli K12 DH5α) and probiotic, Gram-positive bacteria (Lactobacillus rhamnosus GG and Bifidobacterium bifidum) on ZFP secretion in an in vitro model. Additionally, utilizing samples from human clinical trials, we correlated circulating levels of ZFPs to the gut bacteria and determined the presence of ZFPs in various human tissues. Unexpectedly, we found that the ZFPs quantified by the widely used IDK® Zonulin ELISA kits are specifically triggered by the exposure to live Lactobacillus rhamnosus GG in HT-29 cells, associated with absolute abundances of intestinal Lactobacillus and Bifidobacterium in adults, and are copious in the small intestine but undetectable in the liver or adipose tissue. These characteristics appear to be different from zonulin and highlight the need for further characterization of ZFPs recognized by commercially available and widely used “zonulin” ELISAs.

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Serum zonulin measured by enzyme-linked immunosorbent assay may not be a reliable marker of small intestinal permeability in healthy adults

Abstract: Please cite this article as: O. Tatucu-Babet, A. Forsyth, E. Owen, et al., Serum zonulin measured by enzyme-linked immunosorbent assay may not be a reliable marker of small intestinal permeability in healthy adults, Nutrition Research (2020),

Cited by 15 publications

References 39 publications

Fecal Zonulin as a Noninvasive Biomarker of Intestinal Permeability in Pediatric Patients with Inflammatory Bowel Diseases—Correlation with Disease Activity and Fecal Calprotectin

Fecal Zonulin as a Noninvasive Biomarker of Intestinal Permeability in Pediatric Patients with Inflammatory Bowel Diseases—Correlation with Disease Activity and Fecal Calprotectin

Sport Supplements and the Athlete’s Gut: A Review

In vitro Effects of Bacterial Exposure on Secretion of Zonulin Family Peptides and Their Detection in Human Tissue Samples

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