Dietary interventions like gluten-free and casein-free diets have been reported
to improve intestinal, autoimmune and neurological symptoms in patients with a variety of
conditions; however, the underlying mechanism of benefit for such diets remains unclear.
Epigenetic programming, including CpG methylation and histone modifications, occurring
during early postnatal development can influence the risk of disease in later life, and
such programming may be modulated by nutritional factors such as milk and wheat,
especially during the transition from a solely milk-based diet to one that includes other
forms of nutrition. The hydrolytic digestion of casein (a major milk protein) and gliadin
(a wheat-derived protein) releases peptides with opioid activity, and in the present
study, we demonstrate that these food-derived proline-rich opioid peptides modulate
cysteine uptake in cultured human neuronal and gastrointestinal (GI) epithelial cells via
activation of opioid receptors. Decreases in cysteine uptake were associated with changes
in the intracellular antioxidant glutathione and the methyl donor S-adenosylmethionine.
Bovine and human casein-derived opioid peptides increased genome-wide DNA methylation in
the transcription start site region with a potency order similar to their inhibition of
cysteine uptake. Altered expression of genes involved in redox and methylation homeostasis
was also observed. These results illustrate the potential of milk- and wheat-derived
peptides to exert antioxidant and epigenetic changes which may be particularly important
during the postnatal transition from placental to GI nutrition. Differences between
peptides derived from human and bovine milk may contribute to developmental differences
between breastfed and formula-fed infants. Restricted antioxidant capacity, caused by
wheat- and milk-derived opioid peptides, may predispose susceptible individuals to
inflammation and systemic oxidation, partly explaining the benefits of gluten-free or
casein-free diets.