Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers
Article first published online: 6 AUG 2012
Copyright © 2012 EMBO Molecular Medicine
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 4, Issue 9, pages 866–881, September 2012
How to Cite
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. and Shaunak, S. (2012), Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers. EMBO Mol Med, 4: 866–881. doi: 10.1002/emmm.201201290
- Issue published online: 4 SEP 2012
- Article first published online: 6 AUG 2012
- Manuscript Accepted: 22 JUN 2012
- Manuscript Revised: 15 JUN 2012
- Manuscript Received: 15 FEB 2012
- Funded Access
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.
–>See accompanying article http://dx.doi.org/10.1002/emmm.201201668