Table 1.

Studies investigating diseases linked to BCM-7 and A1 milk.

BCM-7 Related Diseases	Study Type	General Results and Outcome	References
Lactose intolerance	In vivo	The A1 milk consumer group generally had higher maldigestion compared to the A2 milk group.	[51]
Bowel-related disease	Randomized controlled trial	Among 387 toddlers, one A2-only milk, and one traditional milk group were created to investigate the gastrointestinal benefits of A2. The A2 milk group’s parents reported less intestinal constipation and increased GI comfort.	[52]
Central nervous system-related diseases	Animal study	The effect of consumption of A1 and A2 caseins on rat behavior was observed with A1/A2 diet groups. Rats fed with A1 casein showed high depressive-related behaviors and disturbance in neurochemical status.	[53]
Digestive discomfort	Randomized double-blind trial	In a small group of individuals (25-45) with lactose intolerance, the A2 milk group showed a lower number of symptoms compared to the traditional milk group.	[54]
Digestive discomfort	Randomized double-blind crossover trial	33 randomly assigned subjects that are 19-50 years old were fed with only A2 β-casein, conventional, lactose-free, and jersey milk. Compared to the group consuming other types of milk, the group consuming A2 had significantly fewer symptoms of abdominal pain, bloating, and diarrhea.	[55]
Inflammation/allergy	Animal study	Specific pathogen-free male BALB/c mice were fed a balanced diet and A1/A1 and A2/A2 β-casein milk for 30 weeks. According to the study, 30 weeks of feeding A1/A1 β-casein milk caused Th2-induced allergic airway inflammation. A2/A2 β-casein milk did not cause inflammation in this airway, but rather played a protective role for allergy and asthma.	[56]
Digestive disorders	Animal study	Aged Balb-c mice were fed with A1A2, A2A2, and standard laboratory pellet diet. The study did not show very specific results, but mice fed A1A2 milk showed an increase in CD3+ T cells involved in epithelial barrier maintenance compared to mice fed A2A2. Especially when the gastrointestinal tract is exposed to A2 β-casein, the aging mouse model has been shown to positively affect intestinal immunology and morphology.	[57]
Lactose intolerance	Randomized double-blind crossover trial	A 5-day study in lactose-intolerant preschool children compared the consumption of traditional (A1A2) milk with milk containing only A2 β-casein. Gastrointestinal symptoms and problems with stool frequency and consistency were reduced and normalized in child subjects fed milk containing only A2 β-casein. Furthermore, pediatric subjects consuming milk containing A2 β-casein had significant increases in serum levels of interleukin-4, immunoglobulins G, E, G1 and glutathione compared to subjects consuming conventional milk.	[58]
Diabetes melitius	Animal study	An animal study was performed to determine the A1 milk consumption (BCM-7 derived) effect on diabetes over generations of rats (starts from F0, ends at F3 generation). At the last F3 generation (week 30), the number of diabetic rates were double in the A1 group compared to the A2 gorup.	[59]
Central nervous system-related diseases	Double-blind randomized cross-study	Levels of GSH according to consumption of A1/A2 milk were investigated from the perspective of association between lower GSH levels and neurodegenerative diseases. It was found that the A1 consumed group showed lower blood GSH levels, potentially suggesting that BCM-7-based GSH disturbance can lead to neurodegenerative diseases and cell differentiation diseases	[50]
Digestive discomfort	Double-blind, randomized crossover study	A Small group of individuals (41 female) divided into two gorups: the A1 and A2 diet groups. The A1 group had abdominal pain and stool consistency, while the A2 diet group did not show such a correlation.	[29]
Bowel-related disease	Animal study	Consumption of A1/A2 milk on mice gut inflammatory response was investigated. A1 milk induced inflammatory cytokines and certain antibodies compared to the A2 diet group.	[60]
Bowel-related disease	Animal study	Consumption of different casein types (A2 A1) and how it alters the gastrointestinal transit were investigated. The A1 consumed group showed a significant delay when compared to the A2 diet group. The opioid-like activity of A1 was a priority in the research.	[31]
Central nervous system-related diseases	Human study	In a study with 90 infants, 37 were breastfed, and 53 were fed cow milk formula. The research indicated that a problem in the elimination of bovine β-casomorphin-7 is a risk factor that hinders the hypothesis of psychomotor development.	[41]
Cardiovascular diseases	Animal study	60 rabbits were fed A1 and A2 caseins for 6 weeks. The samples were collected at weeks 0, 3, and 6. A1 casein produced higher serum cholesterol and the thickness of the aortic lesion was higher in A1-fed rabbits. As a result, A1 casein is an atherogenic compound.	[61]
Diabetes melitius	Comparative study	The study examined the incidence of diabetes in children aged <14 years ol from 10 countries who consumed A1 variant cow milk protein. As a result of the study, especially in Iceland consumption of A1 variant cow milk protein is related to the occurrence of diabetes mellitus.	[62]
Milk allergy	Human study	26 children aged 5-9 years old were fed nutritive casein formula, and their skin reactions to cow’ s milk as a result.	[63]
Milk allergy	Human and in vitro study	14 healthy individuals with no history of cow’s milk allergies were tested. An allergic reaction to histamine release in the presence of BCM-7 has been demonstrated with a reaction on the skin after 15 min.	[64]