Bile acids modulate tight junction structure and barrier function of Caco-2 monolayers via EGFR activation
Abstract
Intestinal and systemic illnesses have been linked to increased gut permeability. Bile acids, whose luminal profile can be altered in human disease, modulate intestinal paracellular permeability. We investigated the mechanism by which selected bile acids increase gut permeability using a validated in vitro model. Human intestinal Caco-2 cells were grown in monolayers and challenged with a panel of bile acids. Transepithelial electrical resistance and luminal-to-basolateral fluxes of 10-kDa Cascade blue-conjugated dextran were used to monitor paracellular permeability. Immunoprecipitation and immunoblot analyses were employed to investigate the intracellular pathway. Redistribution of tight junction proteins was studied by confocal laser microscopy. Micromolar concentrations of cholic acid, deoxycholic acid (DCA), and chenodeoxycholic acid (CDCA) but not ursodeoxycholic acid decreased transepithelial electrical resistance and increased dextran flux in a reversible fashion. Coincubation of 50 muM CDCA or DCA with EGF, anti-EGF monoclonal antibody, or specific src inhibitor 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP-2) abolished the effect. A concentration of 50 muM of either CDCA or DCA also induced EGF receptor phosphorylation, occludin dephosphorylation, and occludin redistribution at the tight junction level in the same time frame and in a reversible fashion. We conclude that selected bile acids modulate intestinal permeability via EGF receptor autophosphorylation, occludin dephosphorylation, and rearrangement at the tight junction level. The effect is mediated by the src family kinases and is abolished by EGF treatment. These data also support the role of bile acids in the genesis of necrotizing enterocolitis and the protective effect of EGF treatment.
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DCA and CDCA modulated intestinal permeability via endothelial growth factor receptor autophosphorylation, OCLN dephosphorylation, and rearrangement at the tight junction level.
“This study concluded that DCA and CDCA modulated intestinal permeability via endothelial growth factor (EGF) receptor autophosphorylation, OCLN dephosphorylation, and rearrangement at the TJ level.110”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [110]
The effects of DCA and CDCA were mediated by the Src family kinases and were abolished by EGF treatment.
“The effects of these bile acids were mediated by the Src family kinases and was abolished by EGF treatment.110”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [110]
Using a Caco-2 cell model, DCA and CDCA, but not UDCA, treatment decreased TEER and increased permeability.
“Using a Caco-2 cell model, Raimondi et al110 showed that DCA and CDCA, but not UDCA, treatment decreased TEER and increased permeability.”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [110]
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- Authors
- Raimondi, F., Santoro, P., Barone, M. V., Pappacoda, S., Barretta, M. L., Nanayakkara, M., Apicella, C., Capasso, L., & Paludetto, R.
- Affiliations
- Federico II University Hospital (IT)
- University of Naples Federico II (IT)
- Venue
- American Journal of Physiology-Gastrointestinal and Liver Physiology
- Publisher
- American Physiological Society
- Published
- 2008-04
- Volume
- 294
- Issue
- 4
- Pages
- G906-G913
- ISSN
- 0193-1857 (ISSN-L)
- 1522-1547
- OpenAlex
- W2134354994
- Cited by
- 286
- References
- 31
- Citations by year
- 2026: 10 · 2025: 24 · 2024: 18 · 2023: 17 · 2022: 27 · 2021: 27 · 2020: 25 · 2019: 26 · 2018: 17 · 2017: 9 · 2016: 9 · 2015: 15 · 2014: 14 · 2013: 10 · 2012: 10
- FWCI
- 6.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- bile acids, tight junctions, intestinal permeability, paracellular permeability, EGF receptor, occludin, chenodeoxycholic acid, deoxycholic acid, cholic acid, ursodeoxycholic acid, Src family kinases, PP2, transepithelial electrical resistance, Caco-2 cell monolayers, necrotizing enterocolitis, epidermal growth factor
- MeSH terms
- Antibodies, Monoclonal, Bile Acids and Salts, Chenodeoxycholic Acid, Deoxycholic Acid, Dextrans, Enzyme Activation, Epidermal Growth Factor, Humans, Intestinal Mucosa, Kinetics, Membrane Proteins, Organometallic Compounds, Organophosphorus Compounds, Permeability, Phosphorylation, Pyrimidines, Electric Impedance, Caco-2 Cells, src-Family Kinases, Tight Junctions, Cholic Acid, Protein Kinase Inhibitors, Occludin, ErbB Receptors
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