title: Beneficial Effects of Anti-Interleukin-6 Antibodies on Impaired Gastrointestinal Motility, Inflammation and Increased Colonic Permeability in a Murine Model of Sepsis Are Most Pronounced When Administered in a Preventive Setup.
abstract: OBJECTIVE
  During sepsis, gastrointestinal ileus, mucosal barrier dysfunction and bacterial translocation are accepted to be important triggers that can maintain or exacerbate the septic state. In the caecal ligation and puncture animal model of sepsis, we demonstrated that systemic and colonic interleukin-6 levels are significantly increased coinciding with an impaired colonic barrier function. We therefore aimed to study the effect of therapeutic or curative administration of anti-IL6 antibodies on overall GI motility, colonic permeability and translocation of intestinal bacteria in blood and mesenteric lymph nodes in the mouse caecal ligation and puncture model.
  
  
  METHODS
  OF-1 mice were randomized to either the preventive or curative protocol, in which they received 1 mg/kg of antibodies to interleukin-6, or its IgG isotype control solution. They subsequently underwent either the caecal ligation and puncture procedure, or sham-surgery. GI motility was assessed 48 h following the procedure, as well as colonic permeability, serum and colon cytokines, colonic tight junction proteins at the mRNA level; cultures of blood and mesenteric lymph nodes were performed.
  
  
  RESULTS
  Preventive administration of anti-interleukin-6 antibodies successfully counteracted the gastrointestinal motility disturbances and impaired colonic barrier function that could be observed in vehicle-treated septic animals. Serum and colonic levels of proinflammatory cytokines were significantly lower when animals were preventively treated with anti-interleukin-6 antibodies. A repetitive injection 24 h later resulted in the most pronounced effects. Curative treatment significantly lowered systemic and colonic inflammation markers while the effects on transit and permeability were unfortunately no longer significant.
  
  
  CONCLUSIONS
  Caecal ligation and puncture resulted in septic ileus with an increased colonic permeability. Antibodies to interleukin-6 were able to ameliorate gastro-intestinal motility, suppress inflammation and normalize the permeability of the colonic wall, with the preventive administration combined with a repeat injection being far more efficacious than the sole preventive or curative one.
authors.affiliation: Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Nullens
authors.affiliation: Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium.
authors.forename: Michael
authors.initials: M
authors.lastname: Staessens
authors.affiliation: Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium.
authors.forename: Cédric
authors.initials: C
authors.lastname: Peleman
authors.affiliation: Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: Plaeke
authors.affiliation: Laboratory of Medical Microbiology, University of Antwerp, Antwerp, Belgium.
authors.forename: Surbhi
authors.initials: S
authors.lastname: Malhotra-Kumar
authors.affiliation: Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium.|Antwerp University Hospital, Department of Gastroenterology and Hepatology, Antwerp, Belgium.
authors.forename: Sven
authors.initials: S
authors.lastname: Francque
authors.affiliation: Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium.
authors.forename: Joris G
authors.initials: JG
authors.lastname: De Man
authors.affiliation: Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium.
authors.forename: Benedicte Y
authors.initials: BY
authors.lastname: De Winter
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects*; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018805:Sepsis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology*; D000093242:Interleukin-6 Inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D016207:Cytokines; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors