MTOR plays an important role in cow's milk allergy-associated behavioral and immunological deficits. (October 2015)

• Record Type: Journal Article
• Authors: Wu, Jiangbo; de Theije, Caroline G.M.; da Silva, Sofia Lopes; van der Horst, Hilma; Reinders, Margot T.M.; Broersen, Laus M.; Willemsen, Linette E.M.; Kas, Martien J.H.; Garssen, Johan; Kraneveld, Aletta D.
• Is Part Of: Neuropharmacology. Volume 97(2015)
• Page Start: 220
• Page End: 232
• Publication Date: 2015-10
• Subjects: Mammalian target of rapamycin (mTOR) -- Autism spectrum disorder (ASD) -- Cow's milk allergy (CMA) -- Rapamycin -- Regulatory T (Treg) cells; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2015.04.035
• Languages: English
• ISSNs: 0028-3908

Abstract

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. Highlights: mTOR pathway is implicated in gut–brain axis of food allergy-induced ASD-like behavior. Food allergy is associated with enhanced mTOR signaling in the brain and gut. mTORC1 inhibitor rapamycin improved the behavioral deficits of allergic mice. Rapamycin reduced mTORC1 activity in the brain and gut of allergic mice. Rapamycin inhibited food allergy and increased the number of Treg cells in the ileum.