Treatment with phenylbutyrate in a pre-clinical trial reduces diarrhea due to enteropathogenic Escherichia coli: link to cathelicidin induction.

Abstract

Treatment of shigellosis in rabbits with phenylbutyrate reduces clinical severity and counteracts down-regulation of cathelicidin (CAP-18) in the large intestinal epithelia. We aimed to further evaluate whether in a rabbit model of enteropathogenic Escherichia coli (EPEC) diarrhea, CAP-18 is down-regulated in the small intestine and if oral phenylbutyrate treatment affects CAP-18 expression, clinical recovery, shedding of EPEC in stool and virulence properties of the isolated colonies. EPEC-induced diarrhea down-regulated CAP-18 in the small intestinal epithelia as revealed by immunohistochemistry. Phenylbutyrate treatment reduced clinical illness, improved histological features of inflammation and up-regulated CAP-18 in the epithelia. Active CAP-18 peptide was also released in the stool as noted in Western blot analysis. Multiplex PCR analysis of total bacterial DNA in the stool showed absence of EPEC specific genes eae and bfpA. Treated rabbits shed rough strains still harboring eae and bfpA genes, which were less potent in binding to HeLa cells and induced delayed onset of diarrhea in new rabbits. In conclusion, EPEC-mediated down-regulation of CAP-18 in the small intestinal epithelia was restored by phenylbutyrate treatment. Upregulation of CAP-18 in the epithelia was accompanied by healing of the epithelial lining, reduced shedding and virulence of EPEC and recovery from diarrhea.

• Authors: Abdullah Al-Mamun, Akhirunnessa Mily, Protim Sarker, Snigdha Tiash, Armando Navarro, Mahmuda Akter, Kaisar Ali Talukder, Mohammad Faizul Islam, Birgitta Agerberth, Gudmundur H Gudmundsson, Alejandro Cravioto, Rubhana Raqib
• Journal: Microbes and infection (Microbes Infect) Vol. 15 Issue 13 Pg. 939-50 (Nov 2013) ISSN: 1769-714X [Electronic] France
• PMID: 24016414 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Chemical References

• Antimicrobial Cationic Peptides
• Immunologic Factors
• Phenylbutyrates
• Cathelicidins

Topics

• Administration, Oral
• Animals
• Antimicrobial Cationic Peptides (antagonists & inhibitors, immunology)
• Bacterial Shedding
• Diarrhea (drug therapy, immunology, microbiology, pathology)
• Disease Models, Animal
• Enteropathogenic Escherichia coli (immunology)
• Escherichia coli Infections (drug therapy, immunology, microbiology, pathology)
• Feces (microbiology)
• Gene Expression Profiling
• Immunologic Factors (therapeutic use)
• Intestine, Small (immunology, pathology)
• Phenylbutyrates (therapeutic use)
• Rabbits
• Treatment Outcome
• Cathelicidins