Casomorphins and Gliadorphins Have Diverse Systemic Effects Spanning Gut, Brain and Internal Organs

Abstract

Food-derived opioid peptides include digestive products derived from cereal and dairy diets. If these opioid peptides breach the intestinal barrier, typically linked to permeability and constrained biosynthesis of dipeptidyl peptidase-4 (DPP4), they can attach to opioid receptors. The widespread presence of opioid receptors spanning gut, brain, and internal organs is fundamental to the diverse and systemic effects of food-derived opioids, with effects being evidential across many health conditions. However, manifestation delays following low-intensity long-term exposure create major challenges for clinical trials. Accordingly, it has been easiest to demonstrate causal relationships in digestion-based research where some impacts occur rapidly. Within this environment, the role of the microbiome is evidential but challenging to further elucidate, with microbiome effects ranging across gut-condition indicators and modulators, and potentially as systemic causal factors. Elucidation requires a systemic framework that acknowledges that public-health effects of food-derived opioids are complex with varying genetic susceptibility and confounding factors, together with system-wide interactions and feedbacks. The specific role of the microbiome within this puzzle remains a medical frontier. The easiest albeit challenging nutritional strategy to modify risk is reduced intake of foods containing embedded opioids. In future, constituent modification within specific foods to reduce embedded opioids may become feasible.

Worldwide research on the health effects of bovine milk containing A1 and A2 β-casein: Unraveling the current scenario and future trends through bibliometrics and text mining

“…Interestingly, CT1 includes publications from ≈2001 to ≈2006 on average, but authors such as Woodford, K.B. and de Noni, I. have returned to the field of study with literature reviews reporting the effect of BCM-7, A1 or A2 bovine milk on health ( Summer et al, 2020 ; Woodford, 2021 ). Apparently, efforts would focus on summarizing the existing evidence and since the increase in original research is low, review articles evaluate the same results and offer similar conclusions.…”

“…Apparently, efforts would focus on summarizing the existing evidence and since the increase in original research is low, review articles evaluate the same results and offer similar conclusions. In the period 2021–2022, six clinical trials, in vitro or in vivo animal studies ( Hohmann et al, 2021 ; Liu et al, 2022 ; Mori et al, 2021 ; Osman et al, 2021 ; Prodhan et al, 2022 ; Ramakrishnan et al, 2020 ) and fourteen reviews, systematic reviews or bibliometric studies were published ( Daniloski et al, 2021a , 2021b ; de Gaudry et al, 2022 ; Fernández-Rico et al, 2022 ; Giribaldi et al, 2022 ; Jaiswal and Worku, 2022 ; Jiménez-Montenegro et al, 2022 ; Kaplan et al, 2022 ; Kay et al, 2021 ; Leischner et al, 2021 ; Li et al, 2022 ; Semwal et al, 2022 ; Thiruvengadam et al, 2021 ; Woodford, 2021 ).

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A2 Milk and BCM-7 Peptide as Emerging Parameters of Milk Quality

“…The suggested path is that of the activation of the opioid receptors in the gut, which could alter its microbial composition, with a subsequent impairment of the gut barrier integrity and bile acid metabolism. Woodford ( 24 ) suggested that the diverse presence of opioid receptors across all major human organs provides insights as to why the effects of A1 β-CN and BCM7 have also been identified in relation to such diversity of organs. This hypothesis has also been supported by a different series of studies ( 22 , 26 ), in which the pro-inflammatory role of the A1 β-CN and its effect have been confirmed, not only at the gastrointestinal level, but also on the endocrinological, neurological and cardiovascular systems.…”

Difficulties in Establishing the Adverse Effects of β-Casomorphin-7 Released from β-Casein Variants—A Review

“…The process releases several amino acids, among them β-Casomorp 7 (BCM-7), a bioactive peptide with a seven amino acid long chain (Tyr 60 -Pro 61 -Phe 62 -P Gly 64 -Pro 65 -Ile 66 ) with opioid characteristics (Figure 1) [31]. In the A2 variant, the peptide bond between isoleucine and proline has more e matic resistance, which makes it difficult for proteases to proceed the cleavage betw positions 66 and 67; on the other hand, chain cleavage occurs in the nine amino acid peptide known as β-Casomorphin-9 (BCM-9) (Tyr 60 -Pro 61 -Phe 62 -Pro 63 -Gly 64 -Pro 65 -Pro 67 -Asn 68 ) (Figure 1), which is considered a potentially bioactive peptide with an pertensive and antioxidant properties [31,32]. In the A2 variant, the peptide bond between isoleucine and proline has more enzymatic resistance, which makes it difficult for proteases to proceed the cleavage between positions 66 and 67; on the other hand, chain cleavage occurs in the nine amino acid long peptide known as β-Casomorphin-9 (BCM-9) (Tyr 60 -Pro 61 -Phe 62 -Pro 63 -Gly 64 -Pro 65 -Ile 66 -Pro 67 -Asn 68 ) (Figure 1), which is considered a potentially bioactive peptide with antihypertensive and antioxidant properties [31,32].…”