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.
authors.affiliation: Departments of Medicine, Infectious Diseases & Immunity, Imperial College London, Hammersmith Hospital, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Teo
authors.forename: Steve M
authors.initials: SM
authors.lastname: Toms
authors.forename: Benoit
authors.initials: B
authors.lastname: Marteyn
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Barata
authors.forename: Peter
authors.initials: P
authors.lastname: Simpson
authors.forename: Karen A
authors.initials: KA
authors.lastname: Johnston
authors.forename: Pamela
authors.initials: P
authors.lastname: Schnupf
authors.forename: Andrea
authors.initials: A
authors.lastname: Puhar
authors.forename: Tracey
authors.initials: T
authors.lastname: Bell
authors.forename: Chris
authors.initials: C
authors.lastname: Tang
authors.forename: Mire
authors.initials: M
authors.lastname: Zloh
authors.forename: Steve
authors.initials: S
authors.lastname: Matthews
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Rendle
authors.forename: Philippe J
authors.initials: PJ
authors.lastname: Sansonetti
authors.forename: Sunil
authors.initials: S
authors.lastname: Shaunak
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018988:Bacterial Translocation / Q000187:drug effects; D050091:Dendrimers / Q000008:administration & dosage*; D003967:Diarrhea / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D004405:Dysentery, Bacillary / Q000188:drug therapy* / Q000473:pathology; D005765:Gastrointestinal Agents / Q000008:administration & dosage*; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000473:pathology; D005944:Glucosamine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D007155:Immunologic Factors / Q000008:administration & dosage; D016209:Interleukin-8 / Q000037:antagonists & inhibitors*; D011817:Rabbits; D012760:Shigella / Q000472:pathogenicity; D000093242:Interleukin-6 Inhibitors
chemical_list: D050091:Dendrimers; D005765:Gastrointestinal Agents; D005944:Glucosamine; D007155:Immunologic Factors; D016209:Interleukin-8; D000093242:Interleukin-6 Inhibitors; C000607946:polypropyletherimine dendrimer glucosamine