Food Allergy-Induced Autism-Like Behavior is Associated with Gut Microbiota and Brain mTOR Signaling

Abstract

Li-Hua Cao,1 Hong-Juan He,1 Yuan-Yuan Zhao,2 Zhen-Zhen Wang,1 Xing-Yuan Jia,3 Kamal Srivastava,4,5 Ming-San Miao,1 Xiu-Min Li4,6 1Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, Henan Province, People’s Republic of China; 2School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, Henan Province, People’s Republic of China; 3Department of Pharmacy, Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, 450046, Henan Province, People’s Republic of China; 4Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY, 10595, USA; 5General Nutraceutical Technology, Elmsford, NY, 10523, USA; 6Department of Otolaryngology, New York Medical College, Valhalla, NY, 10595, USACorrespondence: Xiu-Min Li; Ming-San Miao, Tel [phone], Fax [phone], Email [email protected]; [email protected]: Food allergy-induced autism-like behavior has been increasing for decades, but the causal drivers of this association are unclear. We sought to test the association of gut microbiota and mammalian/mechanistic target of rapamycin (mTOR) signaling with cow’s milk allergy (CMA)-induced autism pathogenesis.Methods: Mice were sensitized intragastrically with whey protein containing cholera toxin before sensitization on intraperitoneal injection with whey-containing alum, followed by intragastric allergen challenge to induce experimental CMA. The food allergic immune responses, ASD-like behavioral tests and changes in the mTOR signaling pathway and gut microbial community structure were performed.Results: CMA mice showed autism-like behavioral abnormalities and several distinct biomarkers. These include increased levels of 5-hydroxymethylcytosine (5-hmC) in the hypothalamus; c-Fos were predominantly located in the region of the lateral orbital prefrontal cortex (PFC), but not ventral; decreased serotonin 1A in amygdala and PFC. CMA mice exhibited a specific microbiota signature characterized by coordinate changes in the abundance of taxa of several bacterial genera, including the Lactobacillus. Interestingly, the changes were accompanied by promoted mTOR signaling in the brain of CMA mice.Conclusion: We found that disease-associated microbiota and mTOR activation may thus play a pathogenic role in the intestinal, immunological, and psychiatric Autism Spectrum Disorder (ASD)-like symptoms seen in CAM associated autism. However, this is only a preliminary study, and their mechanisms require further investigation.Keywords: cow’s milk allergy, autism-like behavior, gut microbiota, mTOR signaling pathway

Keywords

• cow’s milk allergy (cma)
• autism-like behavior
• gut microbiota
• mtor signaling pathway