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Reversal of Pathogen-Induced Barrier Defects in Intestinal Epithelial Cells by Contra-pathogenicity Agents.
- Source :
-
Digestive diseases and sciences [Dig Dis Sci] 2021 Jan; Vol. 66 (1), pp. 88-104. Date of Electronic Publication: 2020 Feb 07. - Publication Year :
- 2021
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Abstract
- Background: Environmental enteropathy (EE) is associated with stunting, impairment of responses to oral vaccines, and other adverse health consequences in young children throughout the developing world. EE is characterized by chronic low-grade intestinal inflammation and disrupted epithelial barrier integrity, partly resulting from dysregulation of tight junction proteins, observed in other enteropathies such as celiac disease. During EE, this dysregulation of tight junction expression amplifies translocation of pathogenic bacteria across the intestinal mucosa.<br />Aims: The aim was to determine whether enteropathogen-mediated epithelial barrier failure can be ameliorated using contra-pathogenicity therapies.<br />Methods: Intestinal epithelial barrier damage was assessed in Caco-2 cells incubated with three important enteropathogens identified in EE patients: Enteropathogenic Escherichia coli (EPEC), Citrobacter rodentium (C. rodentium), and Cryptosporidium parvum (C. parvum). Potential therapeutic molecules were tested to detect effects on transepithelial resistance (TER), bacterial translocation (BT), claudin-4 expression, and regulation of the inflammatory cytokine response.<br />Results: All three enteropathogens compared to uninfected cells, reduced TER (EPEC; p < 0.0001, C. rodentium; p < 0.0001, C. parvum; p < 0.0007), reduced claudin-4 expression, and permitted BT (EPEC; p < 0.0001, C. rodentium; p < 0.0001, C. parvum; p < 0.0003) through the monolayer. Zinc, colostrum, epidermal growth factor, trefoil factor 3, resistin-like molecule-β, hydrocortisone, and the myosin light chain kinase inhibitor ML7 (Hexahydro-1-[(5-iodo-1-naphthalenyl)sulfonyl]-1H-1,4-diazepine hydrochloride); ML7) improved TER (up to 70%) and decreased BT (as much as 96%). Only zinc demonstrated modest antimicrobial activity.<br />Conclusion: The enteropathogens impaired intestinal-epithelial barrier integrity with dysregulation of claudin-4 and increased bacterial translocation. Enteropathogen-mediated damage was reduced using contra-pathogenicity agents which mitigated the effects of pathogens without direct antimicrobial activity.
- Subjects :
- Bacterial Translocation drug effects
Caco-2 Cells
Citrobacter rodentium drug effects
Cryptosporidium parvum drug effects
Enteropathogenic Escherichia coli drug effects
Epidermal Growth Factor pharmacology
Epidermal Growth Factor therapeutic use
Epithelial Cells drug effects
Epithelial Cells microbiology
Humans
Hydrocortisone pharmacology
Hydrocortisone therapeutic use
Intestinal Diseases drug therapy
Intestinal Diseases metabolism
Intestinal Diseases microbiology
Intestinal Mucosa drug effects
Intestinal Mucosa microbiology
Transendothelial and Transepithelial Migration drug effects
Transendothelial and Transepithelial Migration physiology
Bacterial Translocation physiology
Citrobacter rodentium metabolism
Cryptosporidium parvum metabolism
Enteropathogenic Escherichia coli metabolism
Epithelial Cells metabolism
Intestinal Mucosa metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1573-2568
- Volume :
- 66
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Digestive diseases and sciences
- Publication Type :
- Academic Journal
- Accession number :
- 32034605
- Full Text :
- https://doi.org/10.1007/s10620-020-06121-9