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Structural and Functional Changes in the Tight Junctions of Asymptomatic and Serology-negative First-degree Relatives of Patients With Celiac Disease

Mishra, Asha PhD; Prakash, Shyam PhD; Sreenivas, Vishnubhatla PhD; Das, Taposh K. PhD; Ahuja, Vineet DM, MD; Gupta, Siddhartha D. MD; Makharia, Govind K. MD, DM, DNB, MNAMS

Journal of Clinical Gastroenterology: August 2016 - Volume 50 - Issue 7 - p 551–560
doi: 10.1097/MCG.0000000000000436
ALIMENTARY TRACT: Original Articles

Background: Ten to 15% of first-degree relatives (FDRs) of celiac disease (CeD) patients develop CeD. Although intestinal barrier functions (intestinal permeability) are abnormal in the subset of serology-negative FDRs, what leads to the abnormal barrier function is not known.

Goals: To study the ultrastructure and functions of tight junctions in serology-negative FDRs of CeD patients.

Study: The intestinal permeability was measured in 97 asymptomatic and anti-tissue transglutaminase antibody (anti-tTG Ab)-negative FDRs (using the lactulose mannitol ratio) and in 75 controls. The ultrastructure of tight junctions using transmission electron microscopy, and the expression of key tight junction proteins (claudin-2, claudin-3, occludin, JAM-A, and ZO-1) and zonulin using real-time PCR and immunohistochemistry were assessed in anti-tTG Ab-negative, HLA-DQ2/-DQ8-positive FDRs having normal villi and in disease controls. In addition, the serum zonulin level was measured in 172 anti-tTG Ab-negative FDRs and 198 controls.

Results: The intestinal permeability was significantly increased in FDRs than in controls. Ultrastructural abnormalities such as dilatation of the tight junction (P=0.004) and loss of the pentalaminar structure (P=0.001) were more common in FDRs than in disease controls. There was significant underexpression of tight junction proteins ZO-1 (P=0.040) and occludin (P=0.041) in FDRs. There was no significant difference in the serum zonulin level between FDRs and controls (P=0.154).

Conclusions: Even asymptomatic, anti-tTG-Ab-negative FDRs with a normal villous histology have both ultrastructural and functional abnormalities in tight junctions. These findings are indirect evidence of the presence of tight junction abnormalities before the onset of the disease and may have therapeutic implications.

Departments of *Gastroenterology and Human Nutrition



§Pathology, All India Institute of Medical Sciences, New Delhi, India

✠ T.K.D. is now deceased and the copyright is signed by the next of kin on his behalf.

This research was conceptualized, designed, and supervised by G.K.M. and V.A. The study design, participant recruitment, sample collection, performance of experiments, and acquisition of data were performed by A.M. S.P. supervised the HPLC work and the interpretation of data. T.K.D. supervised the acquisition of TEM data. S.D.G. supervised the pathology and IHC work. V.S. performed the biostatistical analysis. Data interpretation and drafting of the manuscript was performed by A.M., G.K.M., V.A., S.D.G., T.K.D., and V.S.

Supported by the Department of Biotechnology, Ministry of Science and Technology, Government of India.

The authors declare that they have nothing to disclose.

Address correspondence to: Govind K. Makharia, MD, DM, DNB, MNAMS, Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India (e-mails:;

Received April 14, 2015

Accepted August 16, 2015

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.