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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 ß-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 ß-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 ß-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 ß-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 ß-casein variant, which is nullified after in vitro digestion. Consequently, we deem BCM-7 unsuitable as a biomarker for food-induced inflammation.

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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, ß-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 ß-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.

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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.

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The possible adverse effect of consuming bovine milk with A1 ß-casein (but not with A2 ß-casein) on health aspects due to the release of ß-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 ß-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.

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Milk can be divided into A1 and A2 types according to ß-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.

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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.

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Lactose maldigesters report an increase in abdominal pain due to the consumption of milk containing a mixture of A1 and A2 ß-casein as compared to milk containing only A2 ß-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 ß-casein and 25% A2 ß-casein and A2 milk containing 100% A2 ß-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 ß-casein and 25% A2 ß-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 ß-casein in the 10 lactose maldigesters. The transit of New-World milk containing A1 and A2 ß-casein was more rapid as compared to Old-World milk containing only A2 ß-casein. This difference in transit may mediate symptoms of lactose intolerance.

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PURPOSE: Food-derived bioactive peptides may influence important physiological functions. An important example is beta-casomorphins, which are opioid peptides derived from A1 beta-casein in bovine milk and have been associated to be risk factors for non-communicable diseases in humans. A1 and A2 beta-casein are different with respect to the release of bioactive peptides, in particular BCM-7. However, evidence from human studies is limited and could be complemented with evidence derived from animal studies. We conducted a scoping review to identify animal studies investigating the effects of A1 beta-casein or BCM-7 compared to A2 beta-casein or any other intervention on health-related outcomes. METHODS: We systematically searched for relevant studies in two electronic databases (Medline, Embase; last search performed March 2020). Two reviewers independently undertook study selection and data extraction of included references. Results were summarized tabularly and narratively. RESULTS: We included 42 studies investigating various animal models, including rats, mice, rabbits, and dogs. Six studies investigated health-related outcomes of A1- vs. A2 milk, while most studies (n = 36) reported on physiological properties (e.g., analgesic effect) of BCM-7 as an opioid peptide. Included studies were extremely heterogeneous in terms of the study population, type of intervention and dose, and type of outcome measures. CONCLUSIONS: Only a few studies comparing the effects of A1- and A2 milk were identified. More studies addressing this research question in animal models are needed to provide essential information to inform research gaps. Results from future studies could eventually complement research for humans, particularly when the body of evidence remains uncertain as is the case in the A1- and A2 milk debate.

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CONTEXT: Various epidemiological studies suggest a positive association between exposure to cow's milk A1 ß-casein protein and risk for noncommunicable chronic diseases. The consumption of A2 cow's milk is increasing, likely because A2 milk is postulated to have positive effects on digestive health. OBJECTIVE: A systematic review was conducted to investigate associations between A1 ß-casein and health-related outcomes in humans. DATA SOURCES: Five electronic databases, 3 clinical trial registries, and the internet were searched systematically. STUDY SELECTION: Using predefined inclusion criteria, 2 authors independently selected studies investigating the effect of A1 ß-casein or ß-casomorphin-7 intake/exposure on any health-related outcome in humans. Discrepancies were resolved by consensus. DATA EXTRACTION: Two authors independently extracted data and assessed risk of bias. The certainty of evidence per outcome was evaluated using the GRADE approach. Discrepancies were resolved by consensus. RESULTS: Fifteen randomized controlled trials, 2 case-control studies, and 8 ecological studies were included. Most randomized controlled studies and case-control studies investigating a potential effect on various outcomes were based on intermediate markers and found no significant difference between the 2 milk types. In contrast, most ecological studies reported that population-level A1 ß-casein exposure is associated with adverse health outcomes. The certainty of the evidence for the included outcomes, as assessed by the GRADE approach, was rated as moderate for digestive symptoms and as low to very low for all other outcomes. CONCLUSIONS: Human-based evidence from clinical trials and epidemiological studies published prior to October 2017 provides moderate certainty for adverse digestive health effects of A1 ß-casein compared with A2 ß-casein but low or very low certainty for other health effects. These conclusions may change in the future, given the emergent nature of this topic and the ongoing research in this area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42016043795.

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