Abnormal transporter and tight junction protein expression in environmental enteric dysfunction

• Published in: The FASEB journal Vol. 36 Suppl 1
• Main Authors: Abtahi, Shabnam, Sailer, Anne, Sadiq, Kamran, Iqbal, Najeeha, Ahmed, Kumail, Kabir, Furqan, Ali, S A, Turner, Jerrold R
• Format: Journal Article
• Language: English
• Published: United States 01.05.2022
• ISSN: 1530-6860
• DOI: 10.1096/fasebj.2022.36.S1.R5615

Environmental enteric dysfunction (EED), which is pervasive in severely underresourced regions with poor sanitation, is characterized by malabsorption and stunted growth and leads to irreversible deficits in physical and intellectual development. Previous studies have associated increased intestinal permeability with EED, but the molecular changes responsible for barrier loss and malabsorption have not been characterized. We sought to define expression of absorptive transport and tight junction proteins using quantitative morphometry of EED patient duodenal biopsies. Biopsies from Pakistani children with confirmed EED diagnoses were compared to those from age-and sex-matched North American healthy controls, celiac disease patients, and non-celiac patients with villous atrophy or intraepithelial lymphocytosis. Claudin-4 expression was increased in EED biopsies relative to all North American subject groups. Claudin-4 expression was most increased within upper villous enterocytes, where it stained lateral membranes and, in EED, accumulated intracellularly. EED biopsies also demonstrated markedly increased occludin expression at tight junctions, lateral membranes, and within vesicular compartments. In contrast, expression of claudin-2, claudin-15, ZO-1, JAM-A, and E-cadherin were similar in EED patients and controls. Villous expression of SGLT1, NHE3, and NaK-ATPase, which drive absorption of glucose, Na , and water, were all increased in EED. In contrast, PEPT1 expression was reduced in EED; expression of CFTR and sucrase isomaltase was unchanged. Increased expression of occludin and claudin-4 were unexpected, as each of these increases tight junction barrier function in vitro. Further, the malabsorption that characterizes EED is at variance with increased SGLT1, NHE3, and NaK-ATPase expression. Although further study is needed, it is possible that these changes represent unsuccessful adaptive responses intended to counteract barrier dysfunction and malabsorption. These data are paradoxical in that they demonstrate that, despite being characterized by malabsorption and barrier dysfunction, EED is associated with increased, rather than reduced, expression of barrier-enhancing tight junction proteins or absorptive proteins. Further study is needed to fully understand the contributions of these alterations to the pathobiology of EED.