Neurological and behavioral symptoms implicate abnormal brain development as a core pathophysiological feature of autism, but increasing evidence also indicates immune [1
] and gastrointestinal (GI) abnormalities in a significant subset [1
]. 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 histone proteins [13
]. These modifications or epigenetic marks favor or disfavor formation of nucleosomes, DNA/histone complexes that maintain genes in a compacted, inactive state (heterochromatin). Methylation of DNA is the most fundamental epigenetic mark, enabling binding of proteins containing methylDNA binding domains, such as methyl CpG binding protein 2 (MeCP2). Proteins with methylDNA binding domains recruit other proteins, including those capable of modifying histones at their tail regions [14
]. Multiple sites and forms of histone modification (e.g., methylation, acetylation, and phosphorylation) make this a highly complex mode of regulation, affected by diverse signaling pathways that adjust gene expression to local cellular metabolic conditions [15
]. Whereas certain epigenetic marks are to some degree reversible, others are not readily reversed and, once in place, these may be sustained for an entire lifespan and/or be transmitted across generations through germline modifications [16
]. Accordingly, epigenetic marking or programming early in development has the potential to exert long-lasting effects [17
There is considerable evidence that epigenetic programming is highly sensitive to changes in the cellular environment, as broadly defined [18
]. Indeed, it appears that epigenetic regulation is a widely utilized adaptive mechanism to allow cells to maintain a favorable metabolic status under different conditions, including differential exposure to physiological substances (e.g., hormones, neurotransmitters, or growth-regulation factors), xenobiotics (e.g., pollutants, toxic chemicals), or even infectious agents (e.g., bacteria or viruses, fungi or parasites) [19
]. Epigenetic regulation may facilitate adaptation to changes in the cellular environment through stable alterations of cellular phenotype, potentially resulting in progressive differentiation and maturation during fetal and possibly postnatal development [20
During prenatal development, nutritional support to the fetus is provided via the transplacental circulation as a function of the available maternal nutriture, with metabolic consequences for both the mother and developing child. During postnatal development, nutritional support is provided by oral food intake into the GI tract: breast-milk- or cow-milk-based formula at first, followed by introduction of other foods, usually in a controlled, gradual manner, but the provision of adequate nutritional resources to support further development of the newborn is not assured. Thus, the prenatal/postnatal transition is a critical juncture in metabolic adaptation. This transition is particularly linked to aerobic metabolism, as the delivery of oxygen via newborn lungs and its ultimate rate of utilization must be balanced by the available antioxidant capacity of body tissues. Epigenetic regulation offers an opportunity for adaptation during this metabolic transition, allowing the level of ongoing aerobic metabolism in each organ system, tissue, and cell type to be maintained in homeostatic equilibrium with antioxidant metabolism.
We use the term postnatal epigenetic programming (PEP) to describe the ongoing adaptive changes in gene expression occurring in response to the transition from fetal to postnatal metabolism, as distinct from prenatal epigenetic programming (PrEP), at term that recognizes the dynamic occurrence of similar changes which occur in utero. While it is clear that autism can result from a variety of genetic and environmental factors, by focusing on factors affecting antioxidant and methylation status in the developing GI tract, immune system, and brain, we hope to illuminate the pathological mechanisms underlying ASDs and other related disorders.