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

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

doi:10.1016/j.micinf.2013.08.007

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

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

Faculty of Life and Environmental Sciences

University of Iceland

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	939-950
Number of pages	12
Journal	Microbes and Infection
Volume	15
Issue number	13
DOIs	https://doi.org/10.1016/j.micinf.2013.08.007
Publication status	Published - Nov 2013

Bibliographical note

Funding Information: This work was supported by the Swedish Agency for Research Cooperation with Developing Countries (Sida/SAREC Agreement support; grant 609 ), Karolinska Institutet , The Swedish Research Council ( 58X-11217-14-3 ), The Swedish Strategic Foundation (SSF), Swedish Cancer Society and the University of Iceland research fund. GHG is a visiting scientist to Karolinska Institutet supported by The Wennergren Foundations. Icddr,b acknowledges with gratitude the commitment of Sida to the Centre's research efforts. Icddr,b also gratefully acknowledges the following donors, which provide unrestricted support to the Center's research efforts: Australian Agency for International Development (AusAID), Government of the People's Republic of Bangladesh, Canadian International Development Agency (CIDA), Embassy of the Kingdom of the Netherlands (EKN), Swedish International Development Cooperation Agency (Sida), Swiss Agency for Development and Cooperation (SDC), and Department for International Development, UK (DFID).

Other keywords

Antimicrobial peptide
CAP-18
Diarrhea
EPEC
Phenylbutyrate
Small intestine

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10.1016/j.micinf.2013.08.007

Cite this

Al-Mamun, A., Mily, A., Sarker, P., Tiash, S., Navarro, A., Akter, M., Talukder, K. A., Islam, M. F., Agerberth, B., Gudmundsson, G. H., Cravioto, A., & Raqib, R. (2013). Treatment with phenylbutyrate in a pre-clinical trial reduces diarrhea due to enteropathogenic Escherichia coli: Link to cathelicidin induction. Microbes and Infection, 15(13), 939-950. https://doi.org/10.1016/j.micinf.2013.08.007

@article{721adbe7ee23475dbc384969e004c05c,

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.",

keywords = "Antimicrobial peptide, CAP-18, Diarrhea, EPEC, Phenylbutyrate, Small intestine",

author = "Abdullah Al-Mamun and Akhirunnessa Mily and Protim Sarker and Snigdha Tiash and Armando Navarro and Mahmuda Akter and Talukder, \{Kaisar Ali\} and Islam, \{Mohammad Faizul\} and Birgitta Agerberth and Gudmundsson, \{Gudmundur H.\} and Alejandro Cravioto and Rubhana Raqib",

note = "Funding Information: This work was supported by the Swedish Agency for Research Cooperation with Developing Countries (Sida/SAREC Agreement support; grant 609 ), Karolinska Institutet , The Swedish Research Council ( 58X-11217-14-3 ), The Swedish Strategic Foundation (SSF), Swedish Cancer Society and the University of Iceland research fund. GHG is a visiting scientist to Karolinska Institutet supported by The Wennergren Foundations. Icddr,b acknowledges with gratitude the commitment of Sida to the Centre's research efforts. Icddr,b also gratefully acknowledges the following donors, which provide unrestricted support to the Center's research efforts: Australian Agency for International Development (AusAID), Government of the People's Republic of Bangladesh, Canadian International Development Agency (CIDA), Embassy of the Kingdom of the Netherlands (EKN), Swedish International Development Cooperation Agency (Sida), Swiss Agency for Development and Cooperation (SDC), and Department for International Development, UK (DFID).",

year = "2013",

month = nov,

doi = "10.1016/j.micinf.2013.08.007",

language = "English",

volume = "15",

pages = "939--950",

journal = "Microbes and Infection",

issn = "1286-4579",

publisher = "Elsevier Masson s.r.l.",

number = "13",

}

Al-Mamun, A, Mily, A, Sarker, P, Tiash, S, Navarro, A, Akter, M, Talukder, KA, Islam, MF, Agerberth, B, Gudmundsson, GH, Cravioto, A & Raqib, R 2013, 'Treatment with phenylbutyrate in a pre-clinical trial reduces diarrhea due to enteropathogenic Escherichia coli: Link to cathelicidin induction', Microbes and Infection, vol. 15, no. 13, pp. 939-950. https://doi.org/10.1016/j.micinf.2013.08.007

TY - JOUR

T1 - Treatment with phenylbutyrate in a pre-clinical trial reduces diarrhea due to enteropathogenic Escherichia coli

T2 - Link to cathelicidin induction

AU - Al-Mamun, Abdullah

AU - Mily, Akhirunnessa

AU - Sarker, Protim

AU - Tiash, Snigdha

AU - Navarro, Armando

AU - Akter, Mahmuda

AU - Talukder, Kaisar Ali

AU - Islam, Mohammad Faizul

AU - Agerberth, Birgitta

AU - Gudmundsson, Gudmundur H.

AU - Cravioto, Alejandro

AU - Raqib, Rubhana

N1 - Funding Information: This work was supported by the Swedish Agency for Research Cooperation with Developing Countries (Sida/SAREC Agreement support; grant 609 ), Karolinska Institutet , The Swedish Research Council ( 58X-11217-14-3 ), The Swedish Strategic Foundation (SSF), Swedish Cancer Society and the University of Iceland research fund. GHG is a visiting scientist to Karolinska Institutet supported by The Wennergren Foundations. Icddr,b acknowledges with gratitude the commitment of Sida to the Centre's research efforts. Icddr,b also gratefully acknowledges the following donors, which provide unrestricted support to the Center's research efforts: Australian Agency for International Development (AusAID), Government of the People's Republic of Bangladesh, Canadian International Development Agency (CIDA), Embassy of the Kingdom of the Netherlands (EKN), Swedish International Development Cooperation Agency (Sida), Swiss Agency for Development and Cooperation (SDC), and Department for International Development, UK (DFID).

PY - 2013/11

Y1 - 2013/11

N2 - 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.

AB - 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.

KW - Antimicrobial peptide

KW - CAP-18

KW - Diarrhea

KW - EPEC

KW - Phenylbutyrate

KW - Small intestine

UR - https://www.scopus.com/pages/publications/84888044719

U2 - 10.1016/j.micinf.2013.08.007

DO - 10.1016/j.micinf.2013.08.007

M3 - Article

C2 - 24016414

SN - 1286-4579

VL - 15

SP - 939

EP - 950

JO - Microbes and Infection

JF - Microbes and Infection

IS - 13

ER -

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

Abstract

Bibliographical note

Other keywords

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