Bovine milk hypothesis: A1 and A2 β casein, BCM-7 and its impact on human health

Introduction

Cow milk is a healthy food which is considered as excellent source of basic human needed minerals, which carries high nutritional value and also a great source of calcium and phosphorous. The composition of cattle milk is more protein in nature and an importance source of various nutrients including carbohydrates and selected micronutrients. (Abdulhadi et. al., 2018) [3] . Cow milk is majorly constituted of proteins like caseins and whey proteins. In India dairy sector has been significantly growing and consistently been top milk producer which contributes to 63.56%. Nutritional makeup of cow's milk varies depending upon the breed, health status and feed supplements which is provided to the cattle and other factors. The major components of milk are water, fat, protein, lactose, and ash. The minor components of milk are sterols, vitamins and minerals, milk pigments and enzymes. So as indigenous cattle is more adapted to climates and conditions like heat-resistance, which provides more nutritious milk compared to the western breeds (Rekha et al., 2018) [5] . [6] . Among the milk protein casein is major source of all amino acids except sulphur containing amino acids. Casein protein constitutes of 35% of α-casein, 30% β variant and 9% of k-casein and remaining is peptides and amino acids. In that β-casein is second abundant and has more essential amino acids. Because of genetic variation bovine β-casein has been more focused area. In 1998 the complete sequence of β-casein was published by (Heck et.al., 2009) [15] . And until now 15 genetic variants of βcasein are been reported and named according to the order A1, A2, A3, B, C, D, E, F, G, H1, H2, I, J, K, L (Andrea et al., 2020) [10]. In principle, each variant differed by onethree amino acids substitutions at different locations but generally β-casein classifies as A1 type (05 variants) and A2 type (10 variants) depending on the proline and histidine amino acid position at 67 th position (Chitra 2022) [7].

A1 and A2 Milk β Casein

A1 milk is produced by the cows of western origin like Holstein Friesian and jersey cattle. A2 milk is produced by the indigenous native cows which are more beneficial compared to the A1 milk (Shreya et al., 2022) [4] . The protein variation of A1 and A2 milk is with casein protein (i.e. mainly β-casein) is solely under the control of genetics.

There are several types of casein proteins like α, β casein with sub variants like A1, A2, B, C and E (Tom 2020) [1] . The milk which contains A1-β casein is called A1 milk and the milk which contains A2 β casein is called A2 milk. A1 milk and A2 milk variant β-case in which differs at 67 th amino acid where due to mutations A1 is linked to histidine A2 is codes for amino acid proline (Monika et al., 2012) [2] . As many of the studies suggested that A1 milk is associated with several health issues like type -1 diabetes, coronary heart disorders and digestive disorders. Some research suggests that during digestion of A1 milk protein variant beta casein can breakdown to BCM-7 like biological peptides. The A1 and A2 β casein is single nucleotide polymorphism found in different breeds, therefore they are considered as potential genetic markers. A1 allele is linked to high milk yield, high fat and protein yield where A2 is linked to reduces serum cholesterol (Alan et al., 2025) [8].

Digestive Effect of A1 and A2 Milk β Casein

When milk is consumed, proteins are degraded into peptides which help in growth of healthy gut microbe environment. These biological peptides are released in intestine further gets absorbed in main bloodstream which shows systemic effects.

On gastrointestinal digestion of β casein releases several bioactive peptides which vary from medium to large size peptides of size (750 -1800kDa). Several studies showed that on intraluminal digestion of A1 β casein releases the opioid peptide like beta-casomorphin-7 (βCM-7) (Alan et al., 2025) [8] whereas digestion of A2 milk releases BCM-9 and a less amount of BCM-7. βCM-7 is a bioactive peptide of seven amino acid which is released on digestion with pepsin, leucine, aminopeptidase and elastase in small intestine which activates morphine like opioid receptors which are present in gastrointestinal tract and immune system while many of the hypothesis suggest that on digestion of A2 β casein does not release the βCM-7.

Epidemiological works suggested that A1 β casein has association with type 1 diabetes (insulin dependent diabetes) is due to βCM-7 is opioid in nature has shown inhibitory effect on human lymphocyte infiltration and also influences gut tolerated lactose intolerance (Elliott et al., 1999) [9] . The βCM-7 has increased effect of pro inflammatory markers, interleukin (IL-4) and histamine in the rat intestinal fluid. The commonly seen variants of casomorphin are BCM 4,5,6,7,8,9 and neocasomorphins-6 and human BCM-4,5,7,8 and αcasomorphin. But BCM-7 is most common part of discussion due to their health impacts (Ecem et. al., 2024) [14] . Many types of research has shown that BCM-7 is not easily digestable in body, and has pro-inflammatory properties which leads various problems like coronary heart diseases, arteriosclerosis, sudden infant death syndrome and type 1 diabetes (Elliott et al., 1999) [9] . BCM-7 can penetrate the gastrointestinal wall and get into blood circulation. causes inflammation high in the duodenum which may decrease absorption of lactose in ileum which manifest as Lactose intolerance. They also reported that BCM-7 induces the inflammatory responses in the gastrointestinal tract by activating the Th2 pathway and increases the myeloperoxidases, monocyte chemo attractant protein-1, antibodies (IgE, IgG, IgG1, IgG2a) and Toll-like receptors 1and 2 into the intestine which causes intolerance. (Sun Jianqin et. al., 2016) [11] . BCM-7 participates in immune related event, which might trigger metabolic disorder like type-1 diabetes. BCM-7 stimulates the production autoantibodies against the GLUT-2 transporters and these autoantibodies inhibit the activity of GLUT-2 which prevents the uptake glucose by the cell. BCM-7 can also disrupts the insulin hormone transmission regulation and impact on insulin action (Ecem et. al., 2024) [14] .

On consumption of cow milk, β casomorphin 7 released by pancreatic elastase by degrading the peptide bond between Ile 66 and His 67 of A1 β casein (Tailford et al., 2003) [13] . rabbit model showed that β casein of both A1 and A2

produced fatty streaks but A1 produced more extensive lesions and thickened fatty streaks in the aortic arch are more. So, such type of caseins ingested by children is more prone for atherosclerosis. (Torreilles and Guerin 1995) [12] . BCM-7 can also trigger the oxidative state within system. Glutathione act as major antioxidant, directly neutralizes the free radicles and reactive oxygen species (ROS). Due to it opioid effect BCM-7 inhibit the uptake of cysteine amino acid into the cell which affects the production of GSH (glutathione). This decreases the GSH levels in blood which could potentially lead to neurodegenerative disease (Ecem et. al., 2024) [14]

Conclusion

India stands for world's largest milk producer, achieved by strategic selection of high yield breeds, improvements in fodder quality and efficient implementation of cattle cross breeding programs. Milk is globally consumed as a rich source of protein and calcium. This A1/ A2 hypothesis plays an important role on public health. The protein variation of A1 and A2 milk is with casein protein (i.e. mainly β-casein)

is solely under the control of genetics. The hypothesis A1 milk is associated with several health issues like type -1 diabetes, coronary heart disorders and digestive disorders.

Most of the in vitro studies showed that A1milk derived BCM-7 has most potential health impacts compared to A2 milk BCM-7. Though there is no scientific evidence of health impacts on human consumption and its part of controversial topic which needs more research and consideration for gaining better information.

References

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