**8. Conclusions**

There is a broad range of evidential material linking food-derived opioids with delayed intestinal transit, intestinal inflammation, intestinal permeability, and an altered microbiome, with this being linked via opioid receptors and some other receptors to conditions affecting many organs. The diverse presence of opioid receptors within human tissue, combined with individual genetic differences, provides an explanation as to why the effects can be diverse. This then links to inflammatory and auto-immune outcomes in those organs. What remains to be elucidated is the precise nature of the interactions and influencing factors. Many auto-immune relationships remain speculative as to cause.

Whereas many of the short-term gu<sup>t</sup> effects of bBCM7 can be investigated within clinical settings of double-blind random treatment-and-control investigations, this is more challenging with GD7 because of the need to isolate GD7 from other protein and nonprotein components of cereals. In relation to the role of the microbiome, elucidation of the role is difficult given the complexity of the system containing direct and indirect effects, multiple interactions, and feedback loops. What is apparent is that the microbiome provides

gut-condition indicators and gut-condition modulators, with this occurring in association with other factors and hence is occurring in a systemic framework. The biosynthesis of human DPP4 within the brush-border of the gu<sup>t</sup> system, combined with bacterial DPP4 linked to the presence of particular bacteria within the microbiome, together with ability to upregulate DPP4 within the sera and other organs, are all likely to be of fundamental importance. When the microbiome is considered an ecological system, which itself is encompassed within a broader human system spanning the gut, brain, and internal organs with which it interacts, then a key question is what are the externally sourced causal modulators and disruptors of that system? It is in that context that more attention needs to be given to the food-derived opioids.

Specific strategies for reducing exposure to bBCM7 and GD7 are two-fold. Bovine BCM7 is relatively easy to remove from the food-system by producing cows that produce A2 rather than A1 beta-casein or alternatively placing more emphasis on milks from other species such as sheep and goats, plus an emphasis on human milk for babies. Removing GD7 from the diet is more difficult because currently it requires removing gluten and hence all cereals containing gluten from the diet. However, technical solutions such as genetic manipulation to alter one or two amino acids within the GD7 sequence may in the future become practical.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The author consults internationally on agrifood systems projects, some of which relate to food-derived opioids. There has been no client support or client pre-publication awareness relating to the writing of this paper.
