## 3 Results
### How Do \(\beta\)CM-7 and the Microbiota Interact in Gut Health and Disease Regulation?
observed in their pilot study that some individuals showed higher levels of fecal calprotectin, a marker of gut inflammation, with consumption of A1 milk [28]. Research conducted by [PERSON] et al. [39] on healthy adults showed that drinking milk containing only the A2 \(\beta\)-casein variant led to a more significant rise in the plasma levels of glutathione (GSH), a key antioxidant, compared to consuming milk with both A1 and A2 \(\beta\)-casein. The authors propose that the peptide \(\beta\)CM-7 may interfere with cysteine absorption--an amino acid essential for glutathione synthesis. Reduced glutathione availability could be associated with elevated oxidative stress and inflammation. Similarly, [PERSON] et al., [32] in a study involving Chinese individuals who reported lactose intolerance, hypothesized that the inflammation observed with A1 \(\beta\)-casein intake might explain the more severe gastrointestinal symptoms seen when compared to A2 milk consumption. Previous studies have also reported increases in inflammatory markers or related mechanisms following exposure to A1 \(\beta\)-casein, including, in addition to the involvement of \(\beta\)CM-7 in glutathione synthesis [39], increased fecal calprotectin [28] and the effects of \(\beta\)CM-7 on oxidative stress [62] by inhibiting cysteine uptake with redox and epigenetic consequences. In this latest study, it is reported that gluten-derived exorphin and \(\beta\)CM-7 share a mechanistic pathway to induce oxidative stress in cultured human intestinal epithelial cells and neuronal cells [62]. \(\beta\)CM-7 is classified as an exorphin because it is an exogenous opioid peptide with the same classification as morphine [39]. Between 30 min and 6 h after \(\beta\)-casein ingestion, \(\beta\)CM-7 is liberated into the intestinal lumen acting as an agonist of \(\mu\)-opioid receptors in enteric neurons. Its affinity for these receptors is due to its structural similarity to endogenous opioid peptides, such as enkephalins and endorphins. characterized for the presence of tyrosine (Tyr) at its N-terminal end [34]. These receptors and their endogenous ligands are implicated in immune-mediated gastrointestinal pathophysiology [58]. Some studies have found that milk with A1 \(\beta\)-casein is associated with increased gastrointestinal symptoms in individuals with milk intolerance [32; 33]. Beyond the enteric nervous system, \(\mu\)-opioid receptors are also present in the central nervous system (CNS), including the cortical and subcortical regions, the brainstem, and the hypothalamus, which regulate homeostasis. \(\beta\)CM-7 can cross the blood-brain barrier and interact with \(\mu\)-opioid receptors in the CNS, potentially inducing effects such as sedation, mild analgesia, and respiratory depression [63]. All of this highlights the complexity of the interaction between \(\beta\)CM-7, \(\mu\)-opioid receptors, and overall health. The opioid system regulates pain, the endocrine response, emotion, memory, and the gastrointestinal function. Sensitivity to \(\beta\)CM-7 depends on the expression of \(\mu\)-opioid receptors in the gastrointestinal tract and nervous system [39]. Elevated levels of \(\beta\)CM-7 have been observed in individuals with autism, suggesting a decreased ability to metabolize this peptide [22; 39; 46]. Some individuals may be more susceptible to its effects, especially those with lactose intolerance [29; 32; 33; 40; 43], irritable bowel syndrome [29], or autism spectrum disorders [22; 46; 47]. In conclusion, individual response to \(\beta\)CM-7 depends on multiple factors, including enzyme activity, intestinal permeability, opioid receptor expression, and genetic predisposition. This complex interaction between \(\beta\)CM-7, \(\mu\)-opioid receptors, and overall health underscores the importance of considering individual variations when studying the effects of A1 \(\beta\)-casein on human health. How Does the Consumption of A1 \(\beta\)-Casein Versus A2 Influence Digestive Health in Different Populations?