title: mTOR plays an important role in cow's milk allergy-associated behavioral and immunological deficits.
abstract: Autism spectrum disorder (ASD) is multifactorial, with both genetic as well as environmental factors working in concert to develop the autistic phenotype. Immunological disturbances in autistic individuals have been reported and a role for food allergy has been suggested in ASD. Single gene mutations in mammalian target of rapamycin (mTOR) signaling pathway are associated with the development of ASD and enhanced mTOR signaling plays a central role in directing immune responses towards allergy as well. Therefore, the mTOR pathway may be a pivotal link between the immune disturbances and behavioral deficits observed in ASD. In this study it was investigated whether the mTOR pathway plays a role in food allergy-induced behavioral and immunological deficits. Mice were orally sensitized and challenged with whey protein. Meanwhile, cow's milk allergic (CMA) mice received daily treatment of rapamycin. The validity of the CMA model was confirmed by showing increased allergic immune responses. CMA mice showed reduced social interaction and increased repetitive self-grooming behavior. Enhanced mTORC1 activity was found in the brain and ileum of CMA mice. Inhibition of mTORC1 activity by rapamycin improved the behavioral and immunological deficits of CMA mice. This effect was associated with increase of Treg associated transcription factors in the ileum of CMA mice. These findings indicate that mTOR activation may be central to both the intestinal, immunological, and psychiatric ASD-like symptoms seen in CMA mice. It remains to be investigated whether mTOR can be seen as a therapeutic target in cow's milk allergic children suffering from ASD-like symptoms.
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands.
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Wu
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands.
authors.forename: Caroline G M
authors.initials: CG
authors.lastname: de Theije
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands; Nutricia Research, Utrecht, The Netherlands.
authors.forename: Sofia Lopes
authors.initials: SL
authors.lastname: da Silva
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands.
authors.forename: Hilma
authors.initials: H
authors.lastname: van der Horst
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands.
authors.forename: Margot T M
authors.initials: MT
authors.lastname: Reinders
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands; Nutricia Research, Utrecht, The Netherlands.
authors.forename: Laus M
authors.initials: LM
authors.lastname: Broersen
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands.
authors.forename: Linette E M
authors.initials: LE
authors.lastname: Willemsen
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Martien J H
authors.initials: MJ
authors.lastname: Kas
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands; Nutricia Research, Utrecht, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Garssen
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands. Electronic address: a.d.kraneveld@uu.nl.
authors.forename: Aletta D
authors.initials: AD
authors.lastname: Kraneveld
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D018932:Chemokine CCL2 / Q000097:blood; D003192:Compulsive Behavior / Q000188:drug therapy / Q000503:physiopathology; D004032:Diet; D004195:Disease Models, Animal; D006120:Grooming / Q000187:drug effects / Q000502:physiology; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008809:Mice, Inbred C3H; D016269:Milk Hypersensitivity / Q000188:drug therapy / Q000503:physiopathology* / Q000523:psychology; D046912:Multiprotein Complexes / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D012919:Social Behavior; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D007166:Immunosuppressive Agents; D046912:Multiprotein Complexes; D012333:RNA, Messenger; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Autism spectrum disorder (ASD); Cow's milk allergy (CMA); Mammalian target of rapamycin (mTOR); Rapamycin; Regulatory T (Treg) cells