Novel mechanistic explanation for use of gluten free casein free diet in Autism spectrum disorder

Abstract

Parents of autistic children report cognitive and behavioral improvement upon removal of casein and gluten (GF/CF) from their child’s diet. Peptides like ?-casomorphin-7 (?CM7) and ?-gliadin-7 (?G7) are formed after ingestion of milk and wheat/rye, respectively, which can activate opiate receptors at low concentrations. Systemic oxidative stress i.e. decreased antioxidant glutathione (GSH) is also reported by previous work in our lab. Cysteine availability through excitatory amino acid transporter-3 (EAAT3) is rate-limiting for GSH synthesis in both neurons and intestinal epithelial cells. ææWe investigated effects of these opioid drugs and their mechanism of influence on pathways of sulfur metabolism, redox and global and CpG site-specific DNA methylation status along with genome wide microarray in cultured neuronal cells. We found that bovine BCM-7 inhibited the EAAT3 activity, which transports cysteine. Subsequent decreases in the GSH/GSSG and SAM/SAH ratios were also observed. Global DNA methylation measured as an index of 5-Methyl Cytosine levels, and Site-specific CpG methylation, indicated large changes in genome wide promoter methylation levels. Further, genome wide microarray analysis and a focused gene array qRTPCR assay confirmed the temporal differences in the affects of bovine BCM-7 to human form of BCM-7 on epigenetic changes. æææThe current study is the first study to link casein/gluten derived peptides to epigenetic changes in autism, and provides a novel mechanistic explanation for the benefit of GF/CF dietary intervention for the treatment of autism and other inflammatory disorder.