Although autism is first and foremost a disorder of the central nervous system, comorbid dysfunction of the gastrointestinal (GI) and immune systems is common, suggesting that all three systems may be affected by common molecular mechanisms. Substantial systemic deficits in the antioxidant glutathione and its precursor, cysteine, have been documented in autism in association with oxidative stress and impaired methylation. DNA and histone methylation provide epigenetic regulation of gene expression during prenatal and postnatal development. Prenatal epigenetic programming (PrEP) can be affected by the maternal metabolic and nutritional environment, whereas postnatal epigenetic programming (PEP) importantly depends upon nutritional support provided through the GI tract. Cysteine absorption from the GI tract is a crucial determinant of antioxidant capacity, and systemic deficits of glutathione and cysteine in autism are likely to reflect impaired cysteine absorption. Excitatory amino acid transporter 3 (EAAT3) provides cysteine uptake for GI epithelial, neuronal, and immune cells, and its activity is decreased during oxidative stress. Based upon these observations, we propose that neurodevelopmental, GI, and immune aspects of autism each reflect manifestations of inadequate antioxidant capacity, secondary to impaired cysteine uptake by the GI tract. Genetic and environmental factors that adversely affect antioxidant capacity can disrupt PrEP and/or PEP, increasing vulnerability to autism. 1. Introduction Neurological and behavioral symptoms implicate abnormal brain development as a core pathophysiological feature of autism, but increasing evidence also indicates immune [1–8] and gastrointestinal (GI) abnormalities in a significant subset [1, 8–12]. This triad of dysfunctional systems provides not only a more complete description of autism and autism spectrum disorders (ASDs), but also an important opportunity to consider the mechanisms which could result in the shared involvement of these three particular systems, especially in the context of development. Recent elucidation of the central role of epigenetic regulation of gene expression in development presents a molecular framework within which prenatal and postnatal maturation of neuronal, immune, and GI systems can be viewed. As all cells possess the same DNA, their differentiation into various cell types reflects stable suppression of some genes and activation of others, accomplished in large part by epigenetic regulation. Such regulation involves reversible modifications of both DNA nucleotides and
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