title: Intestinal inflammation in a murine model of autism spectrum disorders.
abstract: Autism spectrum disorder (ASD) is a cluster of neurodevelopmental disorders characterized by impairments in communication, social interest and stereotypical behaviour. Dysfunction of the intestinal tract is reported in patients with ASD and implicated in the development and severity of ASD symptoms. However, more research is required to investigate the association of intestinal problems with ASD and the potential underlying mechanisms. The purpose of this study was to investigate comorbid symptoms of intestinal inflammation in a murine model of ASD induced by prenatal exposure to valproic acid (VPA). Pregnant BALB/c females were treated subcutaneously with 600 mg/kg VPA or phosphate buffered saline on gestational day 11. Offspring were housed with their mother until weaning on postnatal day 21 (P21). All pups were exposed to a social behaviour test on P28. Inflammatory correlates and activity of the serotonergic system were measured in brain and intestinal tissue. Here we demonstrate, in addition to reduced social behaviour and increased expression of neuroinflammatory markers in the brain, that VPA in utero- exposed male offspring showed epithelial cell loss and neutrophil infiltration in the intestinal tract. Furthermore, reduced levels of serotonin were not only observed the prefrontal cortex and amygdala of VPA in utero- exposed males, but also in the small intestine. Overall, we demonstrate that gender-specific inflammatory conditions are present in the small intestines of VPA in utero- exposed mice and are accompanied by a disturbed serotonergic system in the brain as well as in the intestinal tract.
authors: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands. Electronic address: c.g.m.detheije@uu.nl.
authors: Caroline G M
authors: CG
authors: de Theije
authors: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors: Pim J
authors: PJ
authors: Koelink
authors: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors: Gerdien A H
authors: GA
authors: Korte-Bouws
authors: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; Nutricia Research, Uppsalalaan 12, 3584 CT Utrecht, The Netherlands.
authors: Sofia
authors: S
authors: Lopes da Silva
authors: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors: S Mechiel
authors: SM
authors: Korte
authors: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors: Berend
authors: B
authors: Olivier
authors: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; Nutricia Research, Uppsalalaan 12, 3584 CT Utrecht, The Netherlands.
authors: Johan
authors: J
authors: Garssen
authors: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors: Aletta D
authors: AD
authors: Kraneveld
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002659:Child Development Disorders, Pervasive / Q000139:chemically induced / Q000150:complications*; D004195:Disease Models, Animal; D005260:Female; D007079:Ileitis / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011247:Pregnancy; D012701:Serotonin / Q000378:metabolism*; D012919:Social Behavior; D014635:Valproic Acid
chemical_list: D012701:Serotonin; D014635:Valproic Acid
keywords: Autism spectrum disorders; Gut-brain axis; Intestinal tract; Neurodevelopment; Prenatal; Serotonin; Valproic acid