• Sara Nullens, Michael Staessens, Cédric Peleman, Dorien M Schrijvers, Surbhi Malhotra-Kumar, Sven Francque, Gianluca Matteoli, Guy E Boeckxstaens, Joris G De Man, and Benedicte Y De Winter.
• *Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium †Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium ‡Laboratory of Medical Microbiology, University of Antwerp, Antwerp, Belgium §Antwerp University Hospital, Department of Gastroenterology and Hepatology, Antwerp, Belgium ¶Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.
• Shock. 2015 Nov 25.

BackgroundDuring abdominal sepsis, the inhibition of gastrointestinal (GI) motility together with mucosal barrier dysfunction will lead to increased bacterial translocation and maintenance of sepsis. The activation of the vagal anti-inflammatory pathway remains an appealing therapeutic strategy in sepsis. In this respect, selective alpha7 nicotinic acetylcholine receptor (α7nAChR) agonists have shown anti-inflammatory properties in several animal models of inflammation.MethodsSepsis was induced in OF-1 mice by caecal ligation and puncture (CLP). GI transit was quantified, and cytokine levels were determined in serum and colon. Colonic permeability was assessed by means of Evans blue injection. We studied the effect of GTS-21, an α7nAChR agonist on the aforementioned parameters. Splenectomized animals as well as α7nAChR-knock-out animals (Chrna7) were included to study the role of splenic macrophages and the α7nAChR during polymicrobial abdominal sepsis.ResultsIn septic animals, GTS-21 significantly ameliorated GI motility, lowered systemic and colonic levels of IL-6, decreased colonic permeability and decreased the number of positive cultures obtained from blood and mesenteric lymph nodes. Splenectomy prevented animals from developing sepsis-induced ileus. Chrna7 mice displayed a more severe septic phenotype, whereas GTS-21 remarkably was also beneficial in these animals.ConclusionOur results show that peripheral targeting of the vagal anti-inflammatory pathway proves beneficial in an animal model of polymicrobial abdominal sepsis. A major role is allocated to splenic immune cells in the development of sepsis, as preventive splenectomy was protective for the development of sepsis. Data on the Chrna7 mice suggest that the beneficial effects mediated by GTS-21 on inflammation and motility might be related to activation of other receptors besides the α7nAChR.

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