**2. Methodology**

This is a perspectives paper that draws together and thereby integrates evidence relating to systemic effects of casomorphins and gliadorphins, spanning gut, brain, and internal organs. Accordingly, the literature was searched via Google Scholar and PubMed using various combinations of the following keywords: food-derived opioids, beta-casein, casomorphin, gliadorphin, microbiome, microbiota, opioid receptors, beta-casomorphin-7, BCM7, beta-casomorphin-9, gut-to-brain, and various specific internal organs. This literature was then filtered by the author based on manuscript focus. Some background industry information was drawn from the author's professional involvement in agrifood systems spanning farming practices through to human nutrition.

#### **3. The Role of Opioid Receptors**

The widespread presence of opioid receptors spanning gut, brain, internal, and peripheral organs provides a theoretical framework to explain the current evidence and associated postulates laid out in this paper relating to diverse and systemic effects of food-derived opioids. The presence of opioid receptors in the gu<sup>t</sup> and brain became well established in the 1970s [17]. It was also well understood by 1980 that opioid receptors are a key component of internal messaging systems involving endorphins and enkephalins [18]. However, identification of the widespread presence of these receptors in other organs of the body came later [19] and has been an emerging field, linked primarily to identifying and explaining the effects of opioid drugs. There is also now a substantial literature on specific molecular functional mechanisms of the opioid system [20]. This overarching suite of opioid knowledge has been central to understanding the effects that opioid drugs have on a range of internal biological processes, with opioid drugs having potential to not only exhibit inflammatory effects on specific tissues but to also disrupt internal messaging systems. This system disruption then lays a theoretical foundation for immune and auto-immune responses.

Casomorphins were first identified in the late 1970s as having opioid characteristics [9], and this is recognized with the 'morphin' nomenclature. Similarly, opioid peptides within gliadin were clearly identified in the 1980s [11]. However, no prior evidence has been found of extant literature on the presence of opioid receptors as a key element in identifying mechanisms whereby food-derived opioids might themselves have widespread systemic effects that extend well beyond the gu<sup>t</sup> and brain. These concepts will be drawn upon in subsequent sections of the paper.
