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Food-derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences

Malav S. Trivedia, Jayni S. Shaha, Sara Al-Mughairya, Nathaniel W. Hodgsona, Benjamin Simmsa, Geert A. Trooskensb, Wim Van Criekingeb, Richard C. Detha, (2014) The Journal of Nutritional Biochemistry DOI: 10.1016/j.jnutbio.2014.05.004   

Web URL: View this and related abstracts via PubMed here.


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.


These findings show that opioid-like peptides arising from the digestion of the common food proteins gluten (found in wheat and many other grains) and A1 beta-casein (found in ordinary cows' milk) can:
1) reduce the uptake by brain and gut cells of cysteine, needed to make glutathione (important for antioxidant defences), and 
2) affect gene expression in ways that may have important developmental consequences.

As the researchers point out, these effects may have relevance to autism and other developmental conditions, and may help to explain the reported benefits for some individuals of diets free from gluten and casein.

The A2 form of beta-casein found in human breastmilk (and other mammal milks) did not produce the same effects.  This may help to explain why at least some individuals who react badly to cows' milk nonetheless appear to be able to tolerate milk and dairy products derived from other animals, such as such as goats or sheep, which - like human breastmilk - contain the A2 rather than the A1 form of beta-casein.

Read the related news article here:
See also the following events, featuring FAB Research presentations from the lead author, Malav Trivedi:

'Questioning answers' blogspot discussion of the research paper can be found here

And for more information on the differences between A1 and A2 beta-casein, see: