Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers

Ian Teo; Steve M Toms; Benoit Marteyn; Teresa S Barata; Peter Simpson; Karen A Johnston; Pamela Schnupf; Andrea Puhar; Tracey Bell; Chris Tang; Mire Zloh; Steve Matthews; Phillip M Rendle; Philippe J Sansonetti; Sunil Shaunak

doi:10.1002/emmm.201201290

Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers

Ian Teo, Steve M Toms, Benoit Marteyn, Teresa S Barata, Peter Simpson, Karen A Johnston, Pamela Schnupf, Andrea Puhar, Tracey Bell, Chris Tang, Mire Zloh, Steve Matthews, Phillip M Rendle, Philippe J Sansonetti, Sunil Shaunak^*

^*Corresponding author for this work

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

37 Citations (Scopus)

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Abstract

Intestinal pathogens use the host's excessive inflammatory cytokine response, designed to eliminate dangerous bacteria, to disrupt epithelial gut wall integrity and promote their tissue invasion. We sought to develop a non-antibiotic-based approach to prevent this injury. Molecular docking studies suggested that glycosylated dendrimers block the TLR4-MD-2-LPS complex, and a 13.6 kDa polyamidoamine (PAMAM) dendrimer glucosamine (DG) reduced the induction of human monocyte interleukin (IL)-6 by Gram-negative bacteria. In a rabbit model of shigellosis, PAMAM-DG prevented epithelial gut wall damage and intestinal villous destruction, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. Computational modelling studies identified a 3.3 kDa polypropyletherimine (PETIM)-DG as the smallest likely bioactive molecule. In human monocytes, high purity PETIM-DG potently inhibited Shigella Lipid A-induced IL-6 expression. In rabbits, PETIM-DG prevented Shigella-induced epithelial gut wall damage, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. There was no change in β-defensin, IL-10, interferon-β, transforming growth factor-β, CD3 or FoxP3 expression. Small and orally delivered DG could be useful for preventing gut wall tissue damage in a wide spectrum of infectious diarrhoeal diseases.

Original language	English
Pages (from-to)	866-881
Number of pages	16
Journal	EMBO Molecular Medicine
Volume	4
Issue number	9
Early online date	06 Aug 2012
DOIs	https://doi.org/10.1002/emmm.201201290
Publication status	Published - Sept 2012
Externally published	Yes

Bibliographical note

Keywords

Administration, Oral
Animals
Bacterial Translocation/drug effects
Dendrimers/administration & dosage
Diarrhea/drug therapy
Disease Models, Animal
Dysentery, Bacillary/drug therapy
Gastrointestinal Agents/administration & dosage
Gastrointestinal Tract/drug effects
Glucosamine/administration & dosage
Immunologic Factors/administration & dosage
Interleukin-6/antagonists & inhibitors
Interleukin-8/antagonists & inhibitors
Rabbits
Shigella/pathogenicity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/emmm.201201290Licence: CC BY-NC

Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers
Copyright 2012 the authors. This is an open access Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction for non-commercial purposes, provided the author and source are cited.
Final published version, 1.74 MBLicence: CC BY-NC

Cite this

Teo, I., Toms, S. M., Marteyn, B., Barata, T. S., Simpson, P., Johnston, K. A., Schnupf, P., Puhar, A., Bell, T., Tang, C., Zloh, M., Matthews, S., Rendle, P. M., Sansonetti, P. J., & Shaunak, S. (2012). Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers. EMBO Molecular Medicine, 4(9), 866-881. https://doi.org/10.1002/emmm.201201290

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title = "Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers",

abstract = "Intestinal pathogens use the host's excessive inflammatory cytokine response, designed to eliminate dangerous bacteria, to disrupt epithelial gut wall integrity and promote their tissue invasion. We sought to develop a non-antibiotic-based approach to prevent this injury. Molecular docking studies suggested that glycosylated dendrimers block the TLR4-MD-2-LPS complex, and a 13.6 kDa polyamidoamine (PAMAM) dendrimer glucosamine (DG) reduced the induction of human monocyte interleukin (IL)-6 by Gram-negative bacteria. In a rabbit model of shigellosis, PAMAM-DG prevented epithelial gut wall damage and intestinal villous destruction, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. Computational modelling studies identified a 3.3 kDa polypropyletherimine (PETIM)-DG as the smallest likely bioactive molecule. In human monocytes, high purity PETIM-DG potently inhibited Shigella Lipid A-induced IL-6 expression. In rabbits, PETIM-DG prevented Shigella-induced epithelial gut wall damage, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. There was no change in β-defensin, IL-10, interferon-β, transforming growth factor-β, CD3 or FoxP3 expression. Small and orally delivered DG could be useful for preventing gut wall tissue damage in a wide spectrum of infectious diarrhoeal diseases.",

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author = "Ian Teo and Toms, {Steve M} and Benoit Marteyn and Barata, {Teresa S} and Peter Simpson and Johnston, {Karen A} and Pamela Schnupf and Andrea Puhar and Tracey Bell and Chris Tang and Mire Zloh and Steve Matthews and Rendle, {Phillip M} and Sansonetti, {Philippe J} and Sunil Shaunak",

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year = "2012",

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doi = "10.1002/emmm.201201290",

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AU - Teo, Ian

AU - Toms, Steve M

AU - Marteyn, Benoit

AU - Barata, Teresa S

AU - Simpson, Peter

AU - Johnston, Karen A

AU - Schnupf, Pamela

AU - Puhar, Andrea

AU - Bell, Tracey

AU - Tang, Chris

AU - Zloh, Mire

AU - Matthews, Steve

AU - Rendle, Phillip M

AU - Sansonetti, Philippe J

AU - Shaunak, Sunil

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N2 - Intestinal pathogens use the host's excessive inflammatory cytokine response, designed to eliminate dangerous bacteria, to disrupt epithelial gut wall integrity and promote their tissue invasion. We sought to develop a non-antibiotic-based approach to prevent this injury. Molecular docking studies suggested that glycosylated dendrimers block the TLR4-MD-2-LPS complex, and a 13.6 kDa polyamidoamine (PAMAM) dendrimer glucosamine (DG) reduced the induction of human monocyte interleukin (IL)-6 by Gram-negative bacteria. In a rabbit model of shigellosis, PAMAM-DG prevented epithelial gut wall damage and intestinal villous destruction, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. Computational modelling studies identified a 3.3 kDa polypropyletherimine (PETIM)-DG as the smallest likely bioactive molecule. In human monocytes, high purity PETIM-DG potently inhibited Shigella Lipid A-induced IL-6 expression. In rabbits, PETIM-DG prevented Shigella-induced epithelial gut wall damage, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. There was no change in β-defensin, IL-10, interferon-β, transforming growth factor-β, CD3 or FoxP3 expression. Small and orally delivered DG could be useful for preventing gut wall tissue damage in a wide spectrum of infectious diarrhoeal diseases.

AB - Intestinal pathogens use the host's excessive inflammatory cytokine response, designed to eliminate dangerous bacteria, to disrupt epithelial gut wall integrity and promote their tissue invasion. We sought to develop a non-antibiotic-based approach to prevent this injury. Molecular docking studies suggested that glycosylated dendrimers block the TLR4-MD-2-LPS complex, and a 13.6 kDa polyamidoamine (PAMAM) dendrimer glucosamine (DG) reduced the induction of human monocyte interleukin (IL)-6 by Gram-negative bacteria. In a rabbit model of shigellosis, PAMAM-DG prevented epithelial gut wall damage and intestinal villous destruction, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. Computational modelling studies identified a 3.3 kDa polypropyletherimine (PETIM)-DG as the smallest likely bioactive molecule. In human monocytes, high purity PETIM-DG potently inhibited Shigella Lipid A-induced IL-6 expression. In rabbits, PETIM-DG prevented Shigella-induced epithelial gut wall damage, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. There was no change in β-defensin, IL-10, interferon-β, transforming growth factor-β, CD3 or FoxP3 expression. Small and orally delivered DG could be useful for preventing gut wall tissue damage in a wide spectrum of infectious diarrhoeal diseases.

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KW - Animals

KW - Bacterial Translocation/drug effects

KW - Dendrimers/administration & dosage

KW - Diarrhea/drug therapy

KW - Disease Models, Animal

KW - Dysentery, Bacillary/drug therapy

KW - Gastrointestinal Agents/administration & dosage

KW - Gastrointestinal Tract/drug effects

KW - Glucosamine/administration & dosage

KW - Immunologic Factors/administration & dosage

KW - Interleukin-6/antagonists & inhibitors

KW - Interleukin-8/antagonists & inhibitors

KW - Rabbits

KW - Shigella/pathogenicity

U2 - 10.1002/emmm.201201290

DO - 10.1002/emmm.201201290

M3 - Article

C2 - 22887873

SN - 1757-4676

VL - 4

SP - 866

EP - 881

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 9

ER -

Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers

Abstract

Bibliographical note

Keywords

UN SDGs

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