4
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Preoperative administration of the 5-HT4 receptor agonist prucalopride reduces intestinal inflammation and shortens postoperative ileus via cholinergic enteric neurons

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Objectives

          Vagus nerve stimulation (VNS), most likely via enteric neurons, prevents postoperative ileus (POI) by reducing activation of alpha7 nicotinic receptor (α7nAChR) positive muscularis macrophages (mMφ) and dampening surgery-induced intestinal inflammation. Here, we evaluated if 5-HT4 receptor (5-HT4R) agonist prucalopride can mimic this effect in mice and human.

          Design

          Using Ca 2+ imaging, the effect of electrical field stimulation (EFS) and prucalopride was evaluated in situ on mMφ activation evoked by ATP in jejunal muscularis tissue. Next, preoperative and postoperative administration of prucalopride (1–5 mg/kg) was compared with that of preoperative VNS in a model of POI in wild-type and α7nAChR knockout mice. Finally, in a pilot study, patients undergoing a Whipple procedure were preoperatively treated with prucalopride (n=10), abdominal VNS (n=10) or sham/placebo (n=10) to evaluate the effect on intestinal inflammation and clinical recovery of POI.

          Results

          EFS reduced the ATP-induced Ca 2+ response of mMφ, an effect that was dampened by neurotoxins tetrodotoxin and ω-conotoxin and mimicked by prucalopride. In vivo, prucalopride administered before, but not after abdominal surgery reduced intestinal inflammation and prevented POI in wild-type, but not in α7nAChR knockout mice. In humans, preoperative administration of prucalopride, but not of VNS, decreased Il6 and Il8 expression in the muscularis externa and improved clinical recovery.

          Conclusion

          Enteric neurons dampen mMφ activation, an effect mimicked by prucalopride. Preoperative, but not postoperative treatment with prucalopride prevents intestinal inflammation and shortens POI in both mice and human, indicating that preoperative administration of 5-HT4R agonists should be further evaluated as a treatment of POI.

          Trial registration number

          NCT02425774.

          Related collections

          Most cited references37

          • Record: found
          • Abstract: found
          • Article: not found

          5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice.

          Although the mature enteric nervous system (ENS) has been shown to retain stem cells, enteric neurogenesis has not previously been demonstrated in adults. The relative number of enteric neurons in wild-type (WT) mice and those lacking 5-HT(4) receptors [knock-out (KO)] was found to be similar at birth; however, the abundance of ENS neurons increased during the first 4 months after birth in WT but not KO littermates. Enteric neurons subsequently decreased in both WT and KO but at 12 months were significantly more numerous in WT. We tested the hypothesis that stimulation of the 5-HT(4) receptor promotes enteric neuron survival and/or neurogenesis. In vitro, 5-HT(4) agonists increased enteric neuronal development/survival, decreased apoptosis, and activated CREB (cAMP response element-binding protein). In vivo, in WT but not KO mice, 5-HT(4) agonists induced bromodeoxyuridine incorporation into cells that expressed markers of neurons (HuC/D, doublecortin), neural precursors (Sox10, nestin, Phox2b), or stem cells (Musashi-1). This is the first demonstration of adult enteric neurogenesis; our results suggest that 5-HT(4) receptors are required postnatally for ENS growth and maintenance.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Surgical manipulation of the gut elicits an intestinal muscularis inflammatory response resulting in postsurgical ileus.

            To investigate the pathophysiologic mechanisms that lead to ileus after abdominal surgery. The common supposition is that more invasive operations are associated with a more extensive ileus. The cellular mechanisms of postsurgical ileus remain elusive, and few studies have addressed the mechanisms. Rats were subjected to incremental degrees of surgical manipulation: laparotomy, eventration, "running," and compression of the bowel. On postsurgical days 1 and 7, muscularis infiltrates were characterized immunohistochemically. Circular muscle activity was assessed using mechanical and intracellular recording techniques in vitro. Surgical manipulation caused an increase in resident phagocytes that stained for the activation marker lymphocyte function-associated antigen (LFA-1). Incremental degrees of manipulation also caused a progressive increase in neutrophil infiltration and a decrease in bethanechol-stimulated contractions. Compression also caused an increase in other leukocytes: macrophages, monocytes, dendritic cells, T cells, natural killer cells, and mast cells. The data support the hypothesis that the degree of gut paralysis to cholinergic stimulation is directly proportional to the degree of trauma, the activation of resident gut muscularis phagocytes, and the extent of cellular infiltration. Therefore, postsurgical ileus may be a result of an inflammatory response to minimal trauma in which the resident macrophages, activated by physical forces, set an inflammatory response into motion, leading to muscle dysfunction.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Inhibition of macrophage function prevents intestinal inflammation and postoperative ileus in rodents.

              Abdominal surgery results in a molecular and cellular inflammatory response in the intestine, leading to postoperative ileus. It was hypothesised that resident macrophages within the intestinal muscularis have an important role in this local inflammation. To investigate whether chemical or genetic depletion of resident muscularis macrophages would lead to a reduction in the local inflammation and smooth-muscle dysfunction. Two rodent models were used to deplete and inactivate macrophages: (1) a rat model in which resident macrophages were depleted by chlodronate liposomes; (2) a model of mice with osteopetrosis mice, completely lacking the resident muscularis macrophages, used as an additional genetic approach. Animals with normal or altered intestinal macrophages underwent surgical intestinal manipulation. The inflammatory response was investigated by quantitative reverse transcriptase-polymerase chain reaction for mRNA of MIP-1alpha, interleukin (IL)1beta, IL6, intracellular adhesion molecule 1 (ICAM-1) and monocyte chemotractant protein 1 (MCP)-1 in the isolated small bowel muscularis. In addition, muscularis whole mounts were used for histochemical and immunohistochemical analysis to quantify leucocyte infiltration and detect cytokine expression. Subsequently, in vitro muscle contractility and in vivo gastrointestinal transit were measured. Both models resulted in markedly decreased expression of MIP-1alpha, IL1beta, IL6, ICAM-1 and MCP-1 after manipulation compared with controls. In addition to this decrease in inflammatory mediators, recruitment of leucocytes into the muscularis was also diminished. Macrophage-altered animals had near normal in vitro jejunal circular muscle function and gastrointestinal transit despite surgical manipulation. Resident intestinal muscularis macrophages are initially involved in inflammatory responses resulting in postoperative ileus. Depletion and inactivation of the muscularis macrophage network prevents postoperative ileus.
                Bookmark

                Author and article information

                Journal
                Gut
                Gut
                gutjnl
                gut
                Gut
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0017-5749
                1468-3288
                August 2019
                24 November 2018
                : 68
                : 8
                : 1406-1416
                Affiliations
                [1 ] departmentDepartment of Chronic Diseases, Metabolism and Ageing , Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven , Leuven, Belgium
                [2 ] departmentDepartment of Abdominal Surgery , University Hospital of Leuven , Leuven, Belgium
                [3 ] departmentDepartment of Chronic Diseases, Metabolism and Ageing , Translational Research Center for Gastrointestinal Disorders, Laboratory for Mucosal Immunology, University of Leuven , Leuven, Belgium
                [4 ] departmentDepartment of Cellular and Molecular Medicine, Laboratory of Ion Channel Research , KU Leuven; VIB Center for Brain & Disease Research , Leuven, Belgium
                [5 ] departmentDepartment of Anesthesiology , University Hospital of Leuven , Leuven, Belgium
                [6 ] departmentDepartment of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics , Universitiy of Leuven , Leuven, Belgium
                [7 ] departmentCNR, Neuroscience Institute-Milano , Biometra University of Milan , Milan, Italy
                [8 ] departmentDepartment of Pharmaceutical and Pharmacological Sciences, Laboratory for Drug Delivery and Disposition , University of Leuven , Leuven, Belgium
                [9 ] departmentDepartment of Chronic Diseases, Metabolism and Ageing , Translational Research Center for Gastrointestinal Disorders, Laboratory for Enteric Neuroscience, University of Leuven , Leuven, Belgium
                Author notes
                [Correspondence to ] Dr Guy E Boeckxstaens, Department of Chronic Diseases, Metabolism and Ageing; Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven 3000, Belgium; guy.boeckxstaens@ 123456kuleuven.be
                Author information
                http://orcid.org/0000-0002-6229-0045
                Article
                gutjnl-2018-317263
                10.1136/gutjnl-2018-317263
                6691854
                30472681
                6ffcb6af-8308-4d38-ba74-8036714a04d2
                © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 27 July 2018
                : 16 October 2018
                : 18 October 2018
                Funding
                Funded by: European Research Council (ERC) Advanced Grant;
                Funded by: Flanders Fund for Innovation by Science and Technology;
                Funded by: FundRef http://dx.doi.org/10.13039/501100004040, KU Leuven;
                Funded by: FundRef http://dx.doi.org/10.13039/501100003130, Fonds Wetenschappelijk Onderzoek;
                Categories
                Neurogastroenterology
                1506
                2312
                Original article
                Custom metadata
                unlocked

                Gastroenterology & Hepatology
                prucalopride,ileus,enteric neuron,macrophages,anti-inflammatory
                Gastroenterology & Hepatology
                prucalopride, ileus, enteric neuron, macrophages, anti-inflammatory

                Comments

                Comment on this article