A molecular mechanism for the benefit of a gluten-free/casein-free dietary intervention in autism, celiac disease and other inflammatory disorders

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. Blood and urine samples from autistic and schizophrenic patients contain higher amounts of these peptides, suggesting a possible contribution to these disorders. Systemic oxidative stress and brain neuroinflammation have been described in autistic subjects, in association with significantly lower plasma levels of the antioxidant glutathione (GSH). Cysteine availability through excitatory amino acid transporter-3 (EAAT3) is rate-limiting for GSH synthesis in both neurons and intestinal epithelial cells. Here we demonstrate the ability of ?G7, as well as human and bovine forms of ?CM-7 to potently inhibit cysteine uptake in cultured cells. The acute inhibition was similar to the effect of morphine, but less extensive, and was blocked by the opiate antagonist naltrexone, confirming opiate receptor involvement. This inhibition was also associated with significant changes in intracellular thiol levels, including a decrease in the level of GSH. Time-course studies revealed a complex pattern of inhibition and recovery, eventually leading to sustained inhibition. The bovine form of ?CM-7 was more effective than the human form in inhibiting cysteine uptake and altering thiol metabolite levels. DNA methylation analysis indicated global epigenetic changes induced by these peptides. The current study provides a novel mechanistic explanation for the benefit of GF/CF dietary intervention for the treatment of autism and other inflammatory disorders.