title: 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.affiliation: International Centre for Diarrhoeal Disease Research, Bangladesh, 1212 Dhaka, Bangladesh.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Al-Mamun
authors.forename: Akhirunnessa
authors.initials: A
authors.lastname: Mily
authors.forename: Protim
authors.initials: P
authors.lastname: Sarker
authors.forename: Snigdha
authors.initials: S
authors.lastname: Tiash
authors.forename: Armando
authors.initials: A
authors.lastname: Navarro
authors.forename: Mahmuda
authors.initials: M
authors.lastname: Akter
authors.forename: Kaisar Ali
authors.initials: KA
authors.lastname: Talukder
authors.forename: Mohammad Faizul
authors.initials: MF
authors.lastname: Islam
authors.forename: Birgitta
authors.initials: B
authors.lastname: Agerberth
authors.forename: Gudmundur H
authors.initials: GH
authors.lastname: Gudmundsson
authors.forename: Alejandro
authors.initials: A
authors.lastname: Cravioto
authors.forename: Rubhana
authors.initials: R
authors.lastname: Raqib
mesh_terms: D000284:Administration, Oral; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000037:antagonists & inhibitors* / Q000276:immunology*; D057138:Bacterial Shedding; D003967:Diarrhea / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D004195:Disease Models, Animal; D054308:Enteropathogenic Escherichia coli / Q000276:immunology*; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D005243:Feces / Q000382:microbiology; D020869:Gene Expression Profiling; D007155:Immunologic Factors / Q000627:therapeutic use*; D007421:Intestine, Small / Q000276:immunology / Q000473:pathology; D010654:Phenylbutyrates / Q000627:therapeutic use*; D011817:Rabbits; D016896:Treatment Outcome; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D007155:Immunologic Factors; D010654:Phenylbutyrates; D054804:Cathelicidins
keywords: Antimicrobial peptide; CAP-18; Diarrhea; EPEC; Phenylbutyrate; Small intestine