Scientific Report of EFSA prepared by a DATEX Working Group on the potential health impact of β-casomorphins and related peptides

Proteins are a very diverse family of large organic compounds involved in many important biological processes. Following their enzymatic hydrolysis during food processing or digestion, proteins may release fragments from their primary amino acid sequence. These fragments are called peptides, and many of them are known to be physiologically active. The possible beneficial effects of bioactive peptides have attracted increasing interest in recent years. On the other hand, there are also reports suggesting that some food-derived peptides might adversely affect human health. Among these, β-casomorphin-7 (BCM7), a peptide sequence present in the milk protein β-casein, has been suggested to contribute to an increased risk for certain non-communicable diseases, such as autism, cardiovascular diseases and type I diabetes. Some literature reports have proposed possible mechanistic explanations for such associations Recognising the alleged negative effect of BCM7 on human health, EFSA deemed it necessary to perform a comprehensive review of the published scientific literature in order to assess the relationship of this peptide and related peptides with non-communicable diseases. The review covers the following aspects: possible sources of β-casomorphins (BCMs) and related peptides, polymorphism of β-casein, presence of BCMs and related peptides in food before digestion, formation of BCM7 and related peptides during human digestion and the possible molecular interactions of these peptides with the host environment. Furthermore, it covers the absorption and fate of these peptides, including their possible transfer mechanisms across the intestinal epithelium, transport in the blood stream and transfer across the bloodbrain barrier. Finally, possible and suggested organ- and system-specific effects are reviewed, with specific emphasis on the gastrointestinal, central nervous and cardiovascular systems and the suggested link with type 1 diabetes mellitus. This review recognises that proteins, including those present in the diet, are a potential source of a wide range of biologically active peptides, including some with affinity to opioid receptors. The latter are also known as opioid peptides. Opioid peptide sequences have been characterised in animal and plant proteins. To date much work has focused on characterising opioid peptides derived from milk proteins, in particular the caseins. Beta-casomorphins are a group of opioid peptides which can be released from β-casein. The β-casein derived peptide with the sequence Tyr60-Pro61-Phe62-Pro63-Gly64-Pro65-Ile66 is known as β-casomorphin-7. The release of BCM7 through enzymatic digestion of bovine β-casein is dictated by different amino acid sequences of this protein. The sequences vary genetically between cow breeds. The amino acid present in position 67 of the sequence in β-casein appears to be critical for the release of BCM7. In the A2 variant of β-casein a Proline residue occurs at position 67, whereas the A1 and B variants of β-casein have a Histidine residue at this position. In the case of the variants containing Proline the enzymatic hydrolysis of the Ile66-Pro67 bond does not occur or occurs at a very low rate. The proportion of the different protein variants expressed in the milk, including those of β- casein, is related to their allele distributions in the various cattle breeds and populations. Changing selection targets in the last decades has resulted in changes in bovine breedcomposition in most European countries. While no detailed information is available, it is likely that these changes in breed composition have had an impact on milk composition, including protein variants. Taking into account the lack of detailed knowledge in m