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Special attention is given to cow's milk and its variants, with ongoing discussions about health-related impacts primarily focusing on the A1 variant in contrast to the A2 variant. The difference between these variants lies in a single amino acid alteration at position 67 of β-casein. This alteration is presumed to make the A1 variant more susceptible to enzymatic breakdown during milk digestion, leading to an increased release of the peptide β-casomorphin-7 (BCM-7). BCM-7 is hypothesized to interact with µ-opioid receptors on immune cells in humans. Although BCM-7 has demonstrated both immunosuppressive and inflammatory effects, its direct impact on the immune system remains unclear. Thus, we examined the influence of A1 and A2 milk on Concanavalin A (ConA)-stimulated human peripheral blood mononuclear cells (PBMCs), as well as the effect of experimentally digested A1 and A2 milk, containing different amounts of free BCM-7 from β-casein cleavage. Additionally, we evaluated the effects of pure BCM-7 on the proliferation of ConA-stimulated PBMCs and purified CD4+ T cells. Milk fundamentally inhibited PBMC proliferation, independent of the β-casein variant. In contrast, experimentally digested milk of both variants and pure BCM-7 showed no influence on the proliferation of PBMCs or isolated CD4+ T cells. Our results indicate that milk exerts an anti-inflammatory effect on PBMCs, regardless of the A1 or A2 β-casein variant, which is nullified after in vitro digestion. Consequently, we deem BCM-7 unsuitable as a biomarker for food-induced inflammation. [ABSTRACT FROM AUTHOR]

Bovine milk is an essential supplement due to its rich energy- and nutrient-rich qualities. Caseins constitute the vast majority of the proteins in milk. Among these, β-casein comprises around 37% of all caseins, and it is an important type of casein with several different variants. The A1 and A2 variants of β-casein are the most researched genotypes due to the changes in their composition. It is accepted that the A2 variant is ancestral, while a point mutation in the 67th amino acid created the A1 variant. The digestion derived of both A1 and A2 milk is BCM-7. Digestion of A2 milk in the human intestine also forms BCM-9 peptide molecule. The opioid-like characteristics of BCM-7 are highlighted for their potential triggering effect on several diseases. Most research has been focused on gastrointestinal-related diseases; however other metabolic and nervous system-based diseases are also potentially triggered. By manipulating the mechanisms of these diseases, BCM-7 can induce certain situations, such as conformational changes, reduction in protein activity, and the creation of undesired activity in the biological system. Furthermore, the genotype of casein can also play a role in bone health, such as altering fracture rates, and calcium contents can change the characteristics of dietary products. The context between opioid molecules and BCM-7 points to a potential triggering mechanism for the central nervous system and other metabolic diseases discussed. [ABSTRACT FROM AUTHOR]

Simple Summary: This review provides an update on the impact of A1 and A2 milk studies on milk consumption trends. Because it can cause worldwide panic and have very negative economic repercussions, the data from the updated literature must be interpreted extremely carefully. As this paper reveals, there are more in vitro and in vivo animal studies than human clinical trials. Clinical trials are more important because of the subject's significance from the perspective of human health and because of the outcomes of in vitro and animal studies. A new trend in cow's milk has emerged in the market called type A1 and A2 milk. These products have piqued the interest of both consumers and researchers. Recent studies suggest that A2 milk may have potential health benefits beyond that of A1 milk, which is why researchers are investigating this product further. It is interesting to note that the A1 and A2 milk types have area-specific characteristics compared to breed-specific characteristics. Extensive research has focused on milk derivatives obtained from cow's milk, primarily through in vitro and animal studies. However, few clinical studies have been conducted in humans, and the results have been unsatisfactory. New molecular techniques for identifying A1 and A2 milk may help researchers develop new studies that can clarify certain controversies surrounding A1 milk. It is essential to exercise extreme caution when interpreting the updated literature. It has the potential to spread panic worldwide and have negative economic implications. Therefore, this study aims to investigate the differences between A1 and A2 milk in various research areas and clarify some aspects regarding these two types of milk. [ABSTRACT FROM AUTHOR]

This study aimed to determine the polymorphism in 7th exon of beta-casein gene (CSN2) gene in seven domestic (Kosali, Tharparkar, Gangatiri, Sahiwal, Gir, Khariar, Motu) and two exotic cattle breeds (Jersey and Holstein-Friesian). Genomic DNA was extracted from 1000 milk samples, and the C > A polymorphism in CSN2 was determined using the tetra-primer amplification refractory mutation system-polymerase chain reaction method. In all Indigenous cattle breeds, the mean frequency of A1A2 and A2A2 genotypes was 0.19 and 0.80, respectively. The A1A1 genotype was absent in all seven domestic cattle breeds. The frequency of the A2A2 genotype was highest in the Gir breed (0.93). However, the Sahiwal, Tharparkar, and Motu breeds also had a higher frequency of A2A2 genotype compared to other breeds. In contrast, Gangatiri breed of India showed lowest frequency of A2A2 genotype. The mean A1 and A2 allele frequency was 0.09 and 0.91, respectively. In exotic breeds, the mean frequencies of the A1A1, A1A2, and A2A2 genotypes were 0.42, 0.55, and 0.03, respectively. Similarly, the mean A1 and A2 allele frequency was 0.69 and 0.31, respectively. This study suggests the high potential of Gir, Sahiwal, Tharparkar, and Motu cattle for A2 milk production since they carry a favorable A2 genotype. [ABSTRACT FROM AUTHOR]

Special attention is given to cow’s milk and its variants, with ongoing discussions about health-related impacts primarily focusing on the A1 variant in contrast to the A2 variant. The difference between these variants lies in a single amino acid alteration at position 67 of β-casein. This alteration is presumed to make the A1 variant more susceptible to enzymatic breakdown during milk digestion, leading to an increased release of the peptide β-casomorphin-7 (BCM-7). BCM-7 is hypothesized to interact with µ-opioid receptors on immune cells in humans. Although BCM-7 has demonstrated both immunosuppressive and inflammatory effects, its direct impact on the immune system remains unclear. Thus, we examined the influence of A1 and A2 milk on Concanavalin A (ConA)-stimulated human peripheral blood mononuclear cells (PBMCs), as well as the effect of experimentally digested A1 and A2 milk, containing different amounts of free BCM-7 from β-casein cleavage. Additionally, we evaluated the effects of pure BCM-7 on the proliferation of ConA-stimulated PBMCs and purified CD4+ T cells. Milk fundamentally inhibited PBMC proliferation, independent of the β-casein variant. In contrast, experimentally digested milk of both variants and pure BCM-7 showed no influence on the proliferation of PBMCs or isolated CD4+ T cells. Our results indicate that milk exerts an anti-inflammatory effect on PBMCs, regardless of the A1 or A2 β-casein variant, which is nullified after in vitro digestion. Consequently, we deem BCM-7 unsuitable as a biomarker for food-induced inflammation.

Bovine milk is an essential supplement due to its rich energy- and nutrient-rich qualities. Caseins constitute the vast majority of the proteins in milk. Among these, β-casein comprises around 37% of all caseins, and it is an important type of casein with several different variants. The A1 and A2 variants of β-casein are the most researched genotypes due to the changes in their composition. It is accepted that the A2 variant is ancestral, while a point mutation in the 67th amino acid created the A1 variant. The digestion derived of both A1 and A2 milk is BCM-7. Digestion of A2 milk in the human intestine also forms BCM-9 peptide molecule. The opioid-like characteristics of BCM-7 are highlighted for their potential triggering effect on several diseases. Most research has been focused on gastrointestinal-related diseases; however other metabolic and nervous system-based diseases are also potentially triggered. By manipulating the mechanisms of these diseases, BCM-7 can induce certain situations, such as conformational changes, reduction in protein activity, and the creation of undesired activity in the biological system. Furthermore, the genotype of casein can also play a role in bone health, such as altering fracture rates, and calcium contents can change the characteristics of dietary products. The context between opioid molecules and BCM-7 points to a potential triggering mechanism for the central nervous system and other metabolic diseases discussed.

A new trend in cow’s milk has emerged in the market called type A1 and A2 milk. These products have piqued the interest of both consumers and researchers. Recent studies suggest that A2 milk may have potential health benefits beyond that of A1 milk, which is why researchers are investigating this product further. It is interesting to note that the A1 and A2 milk types have area-specific characteristics compared to breed-specific characteristics. Extensive research has focused on milk derivatives obtained from cow’s milk, primarily through in vitro and animal studies. However, few clinical studies have been conducted in humans, and the results have been unsatisfactory. New molecular techniques for identifying A1 and A2 milk may help researchers develop new studies that can clarify certain controversies surrounding A1 milk. It is essential to exercise extreme caution when interpreting the updated literature. It has the potential to spread panic worldwide and have negative economic implications. Therefore, this study aims to investigate the differences between A1 and A2 milk in various research areas and clarify some aspects regarding these two types of milk.

Milk can be divided into A1 and A2 types according to β-casein variants, and there is a debate about whether A1 milk consumption exacerbates gut environments. This study examined the cecum microbiota and fermentation in mice fed A1 casein, A2 casein, mixed casein (commercial casein), soy protein isolate, and egg white. The cecum acetic acid concentration was higher, and the relative abundances of Muribaculaceae and Desulfovibrionaceae were greater in mice fed A1 versus A2 casein. The other parameters of cecum fermentation and microbiota composition were similar among the mice fed A1, A2, and mixed caseins. The differences were more distinctive among the three caseins, soy, and egg feedings. Chao 1 and Shannon indices of the cecum microbiota were lowered in egg white-fed mice, and the microbiota of mice fed milk, soy, and egg proteins were separately grouped by principal coordinate analysis. Mice fed the three caseins were characterized by a high abundance of Lactobacillaceae and Clostridiaceae, those fed soy were characterized by Corynebacteriaceae, Muribaculaceae, and Ruminococcaceae, and those fed egg white were characterized by Eggerthellaceae, Rikenellaceae, and Erysipelatoclostridiaceae. Thus, although several differences can arise between A1 and A2 caseins in terms of their modulatory effects on gut environments, the differences between milk, soy, and egg proteins can be more distinctive and are worth further consideration. [ABSTRACT FROM AUTHOR]

Lactose maldigesters report an increase in abdominal pain due to the consumption of milk containing a mixture of A1 and A2 β-casein as compared to milk containing only A2 β-casein. Gastric transit affects gastrointestinal symptoms and rapid transit has been associated with an increase in abdominal pain. We conducted a double-blinded, randomized, crossover trial in 10 lactose maldigesters. Subjects consumed each of the two types of milk: conventional milk containing 75% A1 β-casein and 25% A2 β-casein and A2 milk containing 100% A2 β-casein. Magnetic resonance images were acquired, and abdominal pain was rated and recorded at 0, 10, 30, 60 and 120 min after milk consumption. The volume of milk in the stomach was calculated using FSL software. The volume of milk in the stomach after consuming milk with 75% A1 β-casein and 25% A2 β-casein was significantly lower at 30 (p = 0.01), 60 (p = 0.002) and 120 (p < 0.001) minutes as compared to milk with 100% A2 β-casein in the 10 lactose maldigesters. The transit of New-World milk containing A1 and A2 β-casein was more rapid as compared to Old-World milk containing only A2 β-casein. This difference in transit may mediate symptoms of lactose intolerance. [ABSTRACT FROM AUTHOR]

The possible adverse effect of consuming bovine milk with A1 β-casein (but not with A2 β-casein) on health aspects due to the release of β-casomorphin-7 (BCM-7) is currently under debate. The aim of this study was to perform a bibliometric analysis of studies extracted from Scopus to explore the relationship between BCM-7, A1 or A2 bovine milk with different aspects of health. Over time, several research groups were formed that are no longer active and although some authors have returned to the field of study, they have focused their efforts mainly on conducting reviews that show the same imprecise conclusions due to the few original articles. Research is concentrated in Europe and Asia, where New Zealand, China and Germany are the countries with the most publications, records and citations on the subject, respectively. On the other hand, no country in Africa or South America has scientific production, which opens the possibility of building collaborations between countries and exploring areas that lack scientific studies. Based on conflicting information from primarily in vitro and animal studies, and limited clinical trials with poor designs, A1 milk presents pro-inflammatory and oxidative activity, but the evidence is insufficient to associate its consumption with negative health effects. However, A2 milk may be better tolerated by the digestive system of some individuals, suggesting its possible modulating role in the intestinal microbiota. Stronger scientific evidence is needed to reach a consensus on whether the presence of β-casein A1 can significantly negatively affect health. The information shown will allow a better understanding of the subject and consumers will be able to make their own decisions regarding A1 or A2 milk.

Lactose maldigesters report an increase in abdominal pain due to the consumption of milk containing a mixture of A1 and A2 β-casein as compared to milk containing only A2 β-casein. Gastric transit affects gastrointestinal symptoms and rapid transit has been associated with an increase in abdominal pain. We conducted a double-blinded, randomized, crossover trial in 10 lactose maldigesters. Subjects consumed each of the two types of milk: conventional milk containing 75% A1 β-casein and 25% A2 β-casein and A2 milk containing 100% A2 β-casein. Magnetic resonance images were acquired, and abdominal pain was rated and recorded at 0, 10, 30, 60 and 120 min after milk consumption. The volume of milk in the stomach was calculated using FSL software. The volume of milk in the stomach after consuming milk with 75% A1 β-casein and 25% A2 β-casein was significantly lower at 30 (p = 0.01), 60 (p = 0.002) and 120 (p < 0.001) minutes as compared to milk with 100% A2 β-casein in the 10 lactose maldigesters. The transit of New-World milk containing A1 and A2 β-casein was more rapid as compared to Old-World milk containing only A2 β-casein. This difference in transit may mediate symptoms of lactose intolerance.

Dairy products from a range of species, including caprine products, have been labelled as A2. Yet these simple terms do not accurately capture the complexity of casein protein sequences or properties, particularly when used to describe non-bovine proteins. This review examines the current state of knowledge of the beta casein (β-CN) proteins in caprine and bovine milk. It explores differences in the naming, sequence and function of caprine and bovine β-CN proteins and questions whether caprine milk can be considered 'A2' or 'A2-like'. None of the twelve caprine β-CN alleles or proteins have been scientifically named 'A2' to date and the caprine β-CN silent allele A1 differs in sequence to bovine β-CN A1. While the bovine β-CN proteins A1 and A2 differ by one amino acid at position 67 (histidine in A1 and proline in A2), all caprine β-CN proteins have proline at this position. These caprine proteins could be considered 'A2-like' based on this criterion alone but there are several other differences in sequence within and outside the β-casomorphin-7 (BCM-7) region that differentiate caprine β-CN proteins from bovine β-CN proteins. These sequence differences in caprine β-CN protein sequence may affect functional properties or the physiological effects of β-casomorphins (BCMs) potentially generated during consumption although there is little information from studies performed to date. Given the current state of understanding of caprine β-CN proteins, it appears inappropriate to label caprine dairy products as 'A2-like'. These knowledge gaps offer promising areas for future research that could provide new insights into the differences between caprine and bovine animals and their milk and dairy products including the bioactivity, functionality and digestibility of different proteins. [Display omitted] • The state of current caprine β-CN diversity and nomenclature is compiled. • No caprine β-CN protein is named A2 and caprine β-CN A1 is distinct from bovine β-CN A1. • Caprine β-CNs have proline at residue 67 but BCM release is unstudied. • Caprine β-CNs differ by at least 19 additional residues from bovine β-CN. • Current data does not support the description of caprine β-CN as 'A2-like'. [ABSTRACT FROM AUTHOR]

Around 35% of the total caseins are β-caseins, which are further classified as A1 β-caseins and A2 β-caseins, based on differences in the amino acid composition of both. A2 is the wild type genetic variant of β-casein while A1 is the mutant. The present study aimed at the isolation of A1 and A2 casein from different cow milk sources and its characterization by using simple chemical techniques, viz. FTIR and spectrofluorimetry. The commercial milk sample from Bos indicus (Gir) (A2) was obtained from Bombay Panjrapole, Mumbai and two commercially available packaged cow milk samples (pasteurized, skimmed) namely from Gokul and Mother Dairy (A1) were also obtained for comparison analysis from the local market. The isolation of casein was performed by standard method and analyzed using SDS-PAGE, FTIR and spectrofluorimetry. There was evidence that the A2 milk lacked histidine and rich in aromatic amino acids like tryptophan using FTIR and spectrofluorimetry techniques.

A number of randomised in vivo trials have to date investigated the health impacts of the genetic variants A1 and A2 of bovine β-casein. The primary difference between these two genetic variants is the mutation leading to an amino acid exchange at a position 67 in the peptide chain. This systematic review evaluated the effects of bovine milk, β-casein and pure β-casomorphin7, in the form of orally administered nutritional ingredients, on possible incidence and risk for chronic digestive discomfort and development of incurable conditions and diseases in human and animal randomised controlled trials. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, searches were performed for publications across 7 electronic databases (Scopus, Embase, Web of Science, Medline, EBSCO, PubMed, and Cochrane) up to and until July 2020, to identify randomised controlled trials. The subsequent search results were screened for relevance firstly by title, then abstract, and the chosen ones by full text, with additional screening of included articles reference lists. In total 2006 peer-reviewed journal articles were identified and after applying exclusion criteria, 19 studies were deemed suitable for inclusion. Human-based and animal-based results from the clinical in vivo studies demonstrated that consumption of A2 β-casein milk can lead to improved tolerance of milk via decline in the ubiquity of gut related discomfort. However, the exact mechanism for these effects or specific individuals that may benefit from A2 β-casein milk as opposed to A1 β-casein milk is still poorly understood. Notably, consumption of A2 β-casein milk had very low to completely no effect on the other health statuses investigated, particularly non-communicable diseases, such as cardiovascular diseases, neurological disorders, and diabetes. Based on current data, there is not sufficient evidence to merit public health authority recommendations related to the consumption and health associations of A1 β-casein milk or A2 β-casein milk. Interestingly, regardless of the scientific evidence between A2 β-casein milk and health, this milk continues to gain prominence on the market, thus further functional research is required to understand the mechanisms of action of these identified peptides and gene variants and any implications A1 or A2 β-casein milk may have on human health and techno-functional properties of milks. [Display omitted] • Impact of β-casein genetic variants on human health from animal and human in vivo studies was systematically analysed. • Both A1 β-casein and A2 β-casein release beta-casomorhin7 during the in vivo digestion. • Consumption of A2 β-casein may decline in perseverance of gut problems, however, not clinically admissible. • Neither A1 β-casein nor A2 β-casein showed an effect on the other health statuses. [ABSTRACT FROM AUTHOR]

Background: Bovine milk contains two types of ß-casein (CSN2); A1 and A2, in which A1 type has shown associations with certain health issues. This study was conducted to identify the abundance of CSN2 A1/A2 variants in European and indigenous dairy breeds in Sri Lanka. Methods: The study included 123 Ayrshire, 101 Holstein Friesian and 92 indigenous White cattle (Bos indicus) populations. Genotyping was performed by PCR-RFLP method using Dde1. Allele and genotype frequencies and population genetic indices were calculated. Result: Results showed A1A2 to be predominant in both Holstein Friesian (0.63) and Ayrshire (0.68) populations while A2A2 (0.82) was predominant in the White cattle population. A1 and A2 allele frequencies were 0.52 and 0.48 in Ayrshire; 0.39 and 0.61 in Holstein Friesian and 0.09 and 0.91 in White cattle populations. Ayrshire and Holstein Friesian populations showed significant deviation from the Hardy-Weinberg equilibrium (p=0.05). When compared to the imported breeds, the White cattle population showed inbreeding and less genetic diversity. [ABSTRACT FROM AUTHOR]

Milk has special significance in Indian mythology, culture and diet. While milk has been considered as a complete food since ages, there are many lobbies, who have been discouraging consumption of milk citing health or cruelty reasons. This review article discusses about the latest controversy about the quality of milk produced by certain exotic breeds of cattle.

The possible adverse effect of consuming bovine milk with A1 β-casein (but not with A2 β-casein) on health aspects due to the release of β-casomorphin-7 (BCM-7) is currently under debate. The aim of this study was to perform a bibliometric analysis of studies extracted from Scopus to explore the relationship between BCM-7, A1 or A2 bovine milk with different aspects of health. Over time, several research groups were formed that are no longer active and although some authors have returned to the field of study, they have focused their efforts mainly on conducting reviews that show the same imprecise conclusions due to the few original articles. Research is concentrated in Europe and Asia, where New Zealand, China and Germany are the countries with the most publications, records and citations on the subject, respectively. On the other hand, no country in Africa or South America has scientific production, which opens the possibility of building collaborations between countries and exploring areas that lack scientific studies. Based on conflicting information from primarily in vitro and animal studies, and limited clinical trials with poor designs, A1 milk presents pro-inflammatory and oxidative activity, but the evidence is insufficient to associate its consumption with negative health effects. However, A2 milk may be better tolerated by the digestive system of some individuals, suggesting its possible modulating role in the intestinal microbiota. Stronger scientific evidence is needed to reach a consensus on whether the presence of β-casein A1 can significantly negatively affect health. The information shown will allow a better understanding of the subject and consumers will be able to make their own decisions regarding A1 or A2 milk., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier B.V.)