Miltefosine treatment reduces visceral hypersensitivity in a rat model for irritable bowel syndrome via multiple mechanisms.

Autor: Botschuijver S; Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands., van Diest SA; Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands., van Thiel IAM; Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands., Saia RS; Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands.; Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil., Strik AS; Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands.; Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands., Yu Z; Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands.; Department of Neurobiology, Tongji Medical College, HUST, Wuhan, People's Republic of China.; State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China., Maria-Ferreira D; Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands.; Departamento de Farmacologia, Setor de Ciências Biológicas, Universidade Federal do Paraná, Curitiba, Brazil., Welting O; Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands., Keszthelyi D; Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands., Jennings G; Business Development, Redivia, Technische Universität, Dresden, Germany., Heinsbroek SEM; Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands.; Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands., Elferink RPO; Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands.; Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands., Schuren FHJ; Microbiology and Systems Biology, The Netherlands Organization for Applied Scientific Research (TNO), Zeist, The Netherlands., de Jonge WJ; Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands.; Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands., van den Wijngaard RM; Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands. R.vandenWijngaard@AMC.UVA.NL.; Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands. R.vandenWijngaard@AMC.UVA.NL.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2019 Aug 29; Vol. 9 (1), pp. 12530. Date of Electronic Publication: 2019 Aug 29.
DOI: 10.1038/s41598-019-49096-y
Abstrakt: Irritable bowel syndrome (IBS) is a heterogenic, functional gastrointestinal disorder of the gut-brain axis characterized by altered bowel habit and abdominal pain. Preclinical and clinical results suggested that, in part of these patients, pain may result from fungal induced release of mast cell derived histamine, subsequent activation of sensory afferent expressed histamine-1 receptors and related sensitization of the nociceptive transient reporter potential channel V1 (TRPV1)-ion channel. TRPV1 gating properties are regulated in lipid rafts. Miltefosine, an approved drug for the treatment of visceral Leishmaniasis, has fungicidal effects and is a known lipid raft modulator. We anticipated that miltefosine may act on different mechanistic levels of fungal-induced abdominal pain and may be repurposed to IBS. In the IBS-like rat model of maternal separation we assessed the visceromotor response to colonic distension as indirect readout for abdominal pain. Miltefosine reversed post-stress hypersensitivity to distension (i.e. visceral hypersensitivity) and this was associated with differences in the fungal microbiome (i.e. mycobiome). In vitro investigations confirmed fungicidal effects of miltefosine. In addition, miltefosine reduced the effect of TRPV1 activation in TRPV1-transfected cells and prevented TRPV1-dependent visceral hypersensitivity induced by intracolonic-capsaicin in rat. Miltefosine may be an attractive drug to treat abdominal pain in IBS.
Databáze: MEDLINE
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