Evaluating the potential of foodborne chemicals to modulate intestinal barrier function: a combined in vitro/in silico toolbox to study the effects on tight junction protein claudin-4.

Authors

Janice Bergen, Christian Fellinger, Magdalena Weinstabl, Maximilian Jobst, Doris Marko, Christian Schröder, Giorgia Del Favero

Published in

Food research international (Ottawa, Ont.). Volume 242. Issue Pt 5. Pages 120021. Oct 31, 2026. Epub Jul 12, 2026.

Abstract

Intestinal barrier integrity is of paramount importance for our health. Several food constituents and contaminants have been described for positive or detrimental effects, however, a correlation between gut associated disorders and xenobiotics exposures remains challenging and modeling options limited. This study presents a NAMs-based hybrid in vitro/in silico workflow to investigate, and eventually prioritize, foodborne xenobiotics for their effect on gut barrier homeostasis. Model compounds comprised endocrine-active chemicals, such as plastic components (bisphenol A, bisphenol F), phytoestrogens (chrysin, daidzein, genistein), mycotoxins (alternariol, zearalenone), and natural/synthetic steroids (17-β-estradiol, cholesterol, levonorgestrel). Plasticizer diisodecyl phthalate was included as foodborne, non-endocrine active substance. The Caco-2/HT29-MTX-E12 intestinal epithelial co-culture was used to design a workflow capable of grasping discrete alterations in tight junction organization. The protein claudin-4 was taken as reference to study the structural organization along cell-cell contacts. Complementarily, docking and molecular dynamics simulations were applied to explore ligand-claudin-4 interactions, providing a pipeline which is potentially suitable to screen larger compounds libraries. Finally, proof-of-principle experiments including repeated exposures to reference compound 17-β-estradiol and plasticizer diisodecyl phthalate, supported the plausibility of a functional impairment of claudin-4. Both compounds significantly increased epithelial permeability without altering cell viability, indicating selective modulation of mechanical barrier properties. Together, this work outlines a mechanistic toolbox for the study of the potential of orally derived xenobiotics in modulating intestinal homeostasis.

PMID:
42637315
Bibliographic data and abstract were imported from PubMed on 25 Aug 2026.

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