Intended for
Health Care
Professionals
• BIOLOGY AND POTENTIAL EFFECTS OF A1
BETA-CASEIN-DERIVED BETA-CASOMORPHIN-7
• BETA-CASEIN AND DIGESTIVE, RESPIRATORY,
AND IMMUNE FUNCTIONS
• BETA-CASEIN VARIANTS AND NEUROLOGICAL CONDITIONS
• BETA-CASEIN PROTEINS AND INFANT GROWTH
AND DEVELOPMENT
BIOLOGY AND
POTENTIAL EFFECTS
OF A1 BETA-CASEIN-DERIVED
BETA-CASOMORPHIN-7
BIOLOGY AND POTENTIAL EFFECTS OF A1 BETA-CASEIN-DERIVED ΒETACASOMORPHIN-7
Executive summary
Cow’s milk and dairy products are a major food source. A major protein component of cow’s
milk is β-casein, of which there are two primary variants, A1 and A2. Digestion of A1 βcasein, but not A2 β-casein, yields the peptide β-casomorphin-7, an exorphin, which can
influence opioid signalling pathways.
Key points
• Digestion of A1 β-casein, but not that of A2 β-casein yields β-casomorphin-7 (BCM-7), an
exogenous opioid peptide (exorphin) that can potently activate opioid receptors
throughout the body
• Opioid receptors are important regulators of signalling processes throughout the body,
including the gastrointestinal tract, immune system, and the central nervous system
• Excessive exposure to A1 β-casein is linked to several clinical disorders, including
abnormal gastrointestinal function, atherosclerosis/ischaemic heart disease, type 1
diabetes, and augmentation of the behavioural symptoms of schizophrenia and autism
• BCM-7 is primarily metabolised by dipeptidyl peptidase 4 (DPP4). Individuals with low
DPP4 activity, particularly infants, are unable to breakdown BCM-7 and experience more
severe symptoms
• Reducing or eliminating the consumption of A1 β-casein, and replacing it with another
major protein source, such as A2 β-casein, may avoid some of these disorders or improve
their symptoms
Introduction
β-casein is a major protein expressed in human and cow’s milk and is present in many food
products derived from milk. In cow’s milk, two primary variants of β-casein, termed A1 and
A2, and several rarer sub-variants have been identified. A1 and A2 β-casein differ in their
protein structure by a substitution of the amino acid at position 67. A1 β-casein contains a
histidine residue at this position, which allows cleavage of the preceding seven amino acid
residues to yield the peptide β-casomorphin-7 (BCM-7) (Figure 1A). A2 β-casein contains a
proline residue, which prevents cleavage of this peptide.1 The sub-variant B β-casein also
has a histidine at position 67, and its cleavage also results in the generation of BCM-7, but
this variant is much less frequent than A1 or A2 β-casein in the milk of cows of European
origin. Nine other variants have been identified to date in the Bos genus (A3, C, D, E, F, G,
H1, H2 and I, of which a histidine occurs at position 67 in variants C, F and G) based on
studies of various breeds of cattle or conducted in different geographical locations, although
these variants are much less common than the A1 and A2 variants.2
The other major peptides formed by the cleavage of β-casein are indicated in Figure
1B. The digestion of β-casein is rapid, and is thought to be completed within about 60 min
under gastro-analogous conditions.3 BCM-7 has the potential to cross the gastrointestinal
wall to enter the systemic circulation, where it may influence systemic and cellular activities
by acting on opioid receptors. BCM-7 may also be able to cross the blood–brain barrier to
influence central nervous system activities. β-casein proteins derived from human breast
milk,4 goat’s milk,5 and sheep’s milk6 are homologous to bovine A2 β-casein,7 based on the
published protein sequences.
Figure 1. (A) Cleavage of A1 β-casein at position 67 yields the peptide β-casomorphin-7. (B)
Other sites within β-casein targeted by gastrointestinal enzymes that yield peptide
molecules. (B) Reprinted from Jinsmaa and Yohiskawa (1999).1
A
B
BCM-7 is an exorphin that influences opioid signalling throughout the body
BCM-7 and other derivatives of β-casein are potent exogenous agonists of opioid receptors
(exorphins), with greatest affinity for µ opioid receptors.8 The role of opioid receptors in
mediating the effects of BCM-7 is supported by the finding that naloxone, a µ opioid
receptor-specific competitive antagonist, prevents many of the effects of BCM-7, including
effects on gastrointestinal motility9, 10 and mucus secretion,11 lymphocyte proliferation,12 and
histamine release from peripheral leukocytes.13 The affinity of bovine BCM-7 to opioid
receptors is approximately 10 times greater than that of human BCM-7, as it requires a 10fold greater naloxone concentration to prevent receptor binding.14
Opioid receptors are expressed by many cell types in most organs. Levels of µ opioid
receptors are highest in the hypothalamus, cerebral cortex, and spleen, moderate in the
cerebellum, intestine, kidney, adrenal, and reproductive organs, and lowest in the lung and
liver. µ opioid receptors are not expressed in the stomach, heart, or endothelium.15, 16 Opioid
receptors are also expressed on inflammatory cells, including lymphocytes and
leukocytes.12, 13
Experimental studies have shown that BCM peptides and analogues may be able to
cross the blood–brain barrier.17-19 This was particularly evident in regions with ‘leaky’
capillaries, such as the pineal gland, the neurohypophysis, and the choroid plexus.19 An
autopsy study revealed BCM immunoreactivity in several brain regions, including the brain
stem20, while a clinical study detected BCM-8 in the cerebrospinal fluid of pregnant and
lactating women.21 Therefore, BCM peptides may influence central signalling pathways after
crossing the blood–brain barrier.
BCM-7 is metabolised by dipeptidyl peptidase 4 (DPP4)
BCM-7, and other related peptides with an amino acid sequence of Tyr-Pro-Phe-Pro-GlyPro-Ile, including their C-terminally shortened fragments, are primarily degraded by DPP4.22
DPP4 is a protease that selectively removes the N-terminal dipeptide from peptides bearing
a Pro or Ala residue at position 2. It is principally expressed on T lymphocytes and a soluble
form exists in plasma.23, 24 A recent study of infants revealed that infants with apparent lifethreatening apnoea had markedly elevated BCM-7 levels but much lower serum DPP4
activity compared with healthy infants of the same age.25 Those results suggested that
individuals with lower DPP4 activity may be more prone to the potential adverse effects of
BCM-7; however, the results need to be confirmed in further studies.
Clinically relevant effects of A1 β-casein and BCM-7
As shown in Figure 2, as BCM-7 has the potential to cross the gastrointestinal wall and
blood–brain barrier, it may be able to influence activities in most systems throughout the
body, partly because of the highly ubiquitous expression of opioid receptors.
Figure 2. A1 β-casein and BCM-7: Production, absorption, and potential targets.
Studies have shown direct effects of BCM-7 on several gastrointestinal functions. For
example, BCM-7 has been reported to reduce the frequency and amplitude of intestinal
contractions, thus slowing gastrointestinal motility,9, 10, 26-28 and to stimulate mucus release.11,
29, 30
BCM-7 also inhibits lamina propria lymphocyte proliferation,12 which may affect
susceptibility to infection.
BCM-7 also has immunomodulatory effects, including triggering of histamine release
from peripheral leukocytes,13 secretagogue effects on peritoneal mast cells,31 and
suppression of lymphocyte proliferation.12 Similarly, A1 β-casein has marked pro-
atherogenic effects, promoting low-density lipoprotein (LDL) oxidation32 and the generation
of autoantibodies to oxidized LDL,33-35 both of which might contribute to the progression of
atherosclerosis.36
A1 β-casein and BCM-7 are also implicated in the pathogenesis of type 1 diabetes
via two mechanisms. In the first, consumption of A1 β-casein induces the production of
autoantibodies that ultimately cause autoimmune-mediated killing of pancreatic β cells.10, 2123
Illustrating the second pathway, A1 β-casein induced diabetes in non-obese diabetogenic
mice via opioid receptors, as the diabetogenic effects of A1 β-casein were prevented by the
µ-receptor-specific antagonist naloxone.37
These immunomodulatory and pro-atherogenic effects of A1 β-casein may be
responsible for the increased risk of increased risk of heart disease (Figure 2A) and type 1
diabetes (Figure 2B) in populations associated with high per capita A1 β-casein
consumption.38
The consumption of β-casein has also been linked with the worsening of symptoms
of schizophrenia39-42 and autism.43-47 These effects were attributed to the opioid activities of
BCM-748 and to oxidative stress,49 causing neurological deficits that manifested as
symptoms of schizophrenia and autism.50
Figure 3. Correlations between A1 β-casein supply per capita in 1990 and ischaemic heart
disease (A) and type 1 diabetes (B). (A) Correlation between A1 β-casein supply per capita
in 1990 and ischaemic heart disease in 1995 in 20 countries. r = 0.76 (95% confidence
interval: 0.48–0.90; p ≤ 0.0001). (B) Correlation between A1 β-casein supply per capita in
1990 and incidence of type 1 diabetes (1990–1994) in children aged 0–14 years in 19
countries. r = 0.92 (95% confidence interval: 0.72–0.97; p < 0.0001). Dotted lines are the
95% confidence limits of the regression line. Reprinted from Laugesen and Elliott (2003).38
A
B
Rationale for avoiding consumption of products containing A1 β-casein
Experimental and small-scale clinical studies, as well as cases in the lay media, have
provided evidence supporting the benefits of removing A1 β-casein from the diet. For
example, switching to a gluten- and casein-free diet ameliorates some of the symptoms of
autism.51-54 Similarly, some food disorders, such as lactose intolerance, may be wrongly
diagnosed and could resolved by replacing A1 β-casein with A2 β-casein.55, 56 Avoidance of
A1 β-casein may also prevent the excess immunomodulatory activity associated with type 1
diabetes, neurological disorders, and ischaemic heart disease. More studies, including
randomized controlled trials, observational cohort studies and case reports, are needed to
confirm the potential clinical benefits of reducing A1 β-casein consumption.
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More in this series
•
Beta-casein and digestive, respiratory and immune functions
•
Beta-casein variants and neurological conditions
•
Beta-casein and infant growth and development
Disclosure
This evidence-based report and others in the same series were developed by the medical
communications branch of Edanz Group Ltd (Hong Kong) to summarize key research
findings associated with bovine A1/A2 β-casein consumption. The reports were
commissioned by A2 Corporation Ltd (Auckland, New Zealand).
BETA-CASEIN AND
DIGESTIVE, RESPIRATORY,
AND IMMUNE FUNCTIONS
BETA-CASEIN AND DIGESTIVE, RESPIRATORY, AND IMMUNE FUNCTIONS
Executive summary
Cow’s milk and dairy products are a major food source. A major protein component of cow’s milk
is β-casein, of which there are two primary variants, A1 and A2. Digestion of A1 β-casein yields
the peptide β-casomorphin-7, an exorphin. β-casomorphin-7 can target opioid receptors in
various systems to influence digestion, respiration, and immunity. Consumption of A2 β-casein
instead of A1 β-casein could have beneficial effects on these systems by avoiding the unwanted
effects of the latter.
Research highlights
•
Digestion of A1 β-casein, but not that of A2 β-casein yields β-casomorphin-7 (BCM-7), an
exogenous opioid peptide (exorphin) that can potently activate opioid receptors
throughout the body
•
Opioid receptors are important regulators of gastrointestinal function, including motility,
mucus secretion and hormone/incretin secretion
•
Casein and its derivatives, including BCM-7, slow gastrointestinal motility, which
may cause constipation
•
BCM-7 significantly increases intestinal mucus secretion via opioid signalling
pathways, which may influence commensal bacteria and drug absorption
•
•
Reducing A1 β-casein consumption could alleviate gastrointestinal disturbances
Many immune cells express the µ-opioid receptor, which has immunosuppressive activity
in vitro and in vivo
•
BCM-7 disturbs immune cell function in vitro
•
Consumption of products containing A2 β-casein, which does not yield BCM-7,
instead of those containing A1 β-casein, could avoid disruption to immune cell
function leading to symptoms of food intolerance
•
Opioid receptors play an important role in controlling respiration
•
Activation of opioid receptors in the brainstem, particularly the pons, can suppress
respiration
•
BCM-7 and other opiates may be involved in apparent life-threatening events in
infants
Introduction
β-casein is a major protein expressed in human and cow’s milk and is present in many food
products derived from milk. In cow’s milk, two primary variants of β-casein, termed A1 and A2,
and several much rarer sub-variants have been identified. A1 and A2 β-casein differ in their
protein structure by a substitution of the amino acid at position 67. A1 β-casein contains a
histidine residue at this position, which allows cleavage of the preceding seven amino acid
residues, generating the peptide β-casomorphin-7 (BCM-7). A2 β-casein contains a proline
residue at this position, which prevents cleavage of this peptide.1 The sub-variant B β-casein
also has a histidine at position 67, and its cleavage also results in the generation of BCM-7, but
this variant is much less frequent than A1 or A2 β-casein in the milk of cows of European origin.
BCM-7 can cross the gastrointestinal wall to enter the systemic circulation and influence
systemic and cellular activities via opioid receptors. Moreover, BCM-7 and other derivatives of
β-casein are potent exogenous agonists—exorphins—for opioid receptors, with the greatest
affinity for µ-opioid receptors.2
Opioid receptors are expressed in many organs, notably the gastrointestinal tract,3, 4
immune cells,5, 6 and the central nervous system, particularly in the regions controlling
respiration.7 Activation of these receptors can have unwanted or unexpected effects on
gastrointestinal, immune, and respiratory functions. Therefore, it is important to evaluate the
potential effects of BCM-7 and related milk-derived peptides on the functions of these systems.
Effects of BCM-7 on intestinal motility
Opioid receptors play a physiologically important role in controlling gastrointestinal function,
including regulating gastrointestinal motility, mucus production and hormone/incretin production.
Several studies have provided direct evidence that casein and its derivatives, particularly BCM
and related peptides, decrease gastrointestinal motility (Figure 1), in part by reducing the
frequency and amplitude of intestinal contractions.8-12 By contrast, soy protein, which cannot be
cleaved to form BCMs, does not exert these effects.9 BCM-7 in particular can mimic the effects
of opioids, in some cases leading to constipation. The role of opioid receptors in mediating
these effects was confirmed, as co-treatment with an opioid receptor antagonist suppressed the
effects of casein.9
Figure 1. A casein protein suspension delays gastric empting (A) and protracts gastrointestinal
transit time (B) compared with a whey protein suspension in rats. (C, D) Naloxone, a specific
opiate receptor antagonist, partially or completely reversed these effects of the casein
suspension, revealing the opioid activity of casein-derived peptides. Reprinted from Daniel et al
(1990).12
CAS = casein protein suspension; WPS = whey protein suspension.
A
#
B
#
C
#
D
#
Effects of BCM-7 on the gut’s immune system: mucus secretion and lymphocyte
activity
Gastrointestinal mucus secretion is at least partly regulated by opioid receptors; it is suppressed
by opioid antagonists, such as naloxone,13 and increased by morphine.14 Gastrointestinal
mucus serves as a protective barrier between the epithelium and the lumen, containing
potentially harmful compounds and microorganisms, as well as a lubricant to help food passage.
15
Studies have shown that dietary peptides, including BCM-7, stimulate mucus release via µ-
opioid receptors (Figure 2).4, 16, 17 Although the clinical relevance of this effect is not fully
understood, excessive mucus secretion may interfere with commensal bacteria18 or alter
gastrointestinal uptake of nutrients or drugs.19
Another component of the gut’s immune system is the lamina propria lymphocytes.
These cells play an important role in innate immunity and protection against pathogens in the
intestinal lumen.20, 21 However, abnormal activity of the gut’s immune system is implicated in the
aetiology of gastrointestinal disorders, such as inflammatory bowel disease21 and food allergies.
22
At least two studies have shown that BCM-7 alters lymphocyte proliferation in vitro through a
pathway mediated by opiate receptors.23, 24 The first of these studies showed suppressive
effects of BCM-7 on lymphocyte proliferation at all concentrations tested, 23while the second
study showed suppressive effects of low BCM-7 doses and stimulatory effects at higher doses.
24
Considering that both studies were performed in vitro, more studies are needed to confirm the
physiological relevance of these immunomodulatory effects of BCM-7 in animals and humans.
Figure 2. BCM-7 significantly enhances mucus secretion in isolated rat jejunum. Reprinted from
Trompette et al (2003).17
#
A1 protein avoidance could lessen gastrointestinal disturbances
The reports described above suggest that the consumption of products containing solely A2 βcasein and exclusion of those containing A1 β-casein could have some health benefits by
maintaining the nutritional benefits associated with milk consumption while excluding the
negative effects of A1 β-casein-derived BCM7 on gastrointestinal function.
One gastrointestinal disorder commonly associated with milk consumption is lactose
intolerance. However, some patients may have food allergy rather than intolerance, or they may
adversely react to other components of milk.25 In this way, reducing or stopping the intake of A1
protein could provide a first step toward isolating the cause of the gastrointestinal disturbance.
Indeed, recent media reports have highlighted this possibility in a child with apparent lactose
intolerance who did not experience gastrointestinal symptoms after switching to products
containing A2 protein, suggesting that this child experienced an immune response to a
component of A1 protein.26, 27
Prospective, randomized controlled studies are needed to confirm the validity of such an
approach, but clinicians should be aware of the effects of BCM-7 on gastrointestinal motility,
mucus secretion and immune function, and could support such a strategy in clinical practice.
Immunomodulatory effects of exorphins
While the immunomodulatory effects of morphine are generally well established, the potential
immunomodulatory effects of β-casein and its cleaved peptides were first identified in the 1980s.
28, 29
Since then, it has become apparent that exorphins, including BCM-7, have
immunomodulatory properties. For example, BCM-7 was reported to trigger histamine release
from peripheral leukocytes 30 and to have secretagogue effects on peritoneal mast cells.31
Studies have shown that BCM-7 alters lymphocyte proliferation in vitro through a pathway
mediated by opiate receptors.23, 24 The first of these studies showed suppressive effects of
BCM-7 on lymphocyte proliferation at all concentrations tested (Figure 3),23 while the second
study showed suppressive effects of low BCM-7 doses and stimulatory effects at higher doses.
24
Clinically, BCM-7 may also stimulate excessive histamine release, resulting in activation
of immune responses30, 32. Impaired immune function may also increase susceptibility to
infection and other potentially severe diseases, as has been reported for morphine.33 Additional
studies are needed to establish the specific immunomodulatory effects of BCM-7 and related
peptides, and to determine their clinical implications.
Figure 3. BCM-7 suppresses thymidine incorporation, as a marker of cell proliferation, in lamina
propria lymphocytes from the colon (black bars) and ileum. *P < 0.05 vs control. Reprinted from
Elitsur et al. (1991).23
#
A1-derived BCM-7 and respiratory function
Opioid receptors, including µ-opioid receptors, are widely expressed in the central nervous
system, including in sites associated with respiration control in the pons.7 Consequently,
activation of these receptors by morphine and other opioids can induce respiratory depression,
which can be reversed by antagonists, such as naloxone.7
Peptides derived from casein, including BCM-7, have been implicated in the aetiology of
sudden infant death syndrome.34 For example, Wasilewska et al. noted that infants with
apparent life-threatening events had higher serum levels of BCM-7 after apnoea compared with
healthy infants of the same age.35 One explanation for their findings was that the level of
dipeptidyl peptidase 4 activity, which degrades short peptides in blood,36 was reduced in these
infants, resulting in abnormally high levels of BCM-7.35 Similar findings were reported for other
BCMs and β-endorphins.37-39 Hedner and Hedner noted that BCMs can readily cross the blood–
brain barrier in newborn rabbits and cause dose-related depressions of respiratory frequency
and tidal volume.40 They found that BCM-7 was equipotent to morphine, and its effects were
reversed or prevented by naloxone, a µ-opioid receptor antagonist.
Further clinical and experimental studies are needed to evaluate the clinical relevance of
BCM-7 in respiratory function and dysfunction in infants and in adults. Studies should also seek
to confirm the association between BCM-7 and apparent life-threatening events in infants, and
whether avoidance of some protein sources could reduce the incidence of such events.
References
1.
Jinsmaa Y, Yoshikawa M. Enzymatic release of neocasomorphin and beta-casomorphin
from bovine beta-casein. Peptides. 1999; 20(8): 957-62.
2.
Koch G, Wiedemann K, Teschemacher H. Opioid activities of human beta-
casomorphins. Naunyn Schmiedebergs Arch Pharmacol. 1985; 331(4): 351-4.
3.
Chen W, Chung HH, Cheng JT. Opiate-induced constipation related to activation of small
intestine opioid mu2-receptors. World J Gastroenterol. 2012; 18(12): 1391-6.
4.
Zoghbi S, Trompette A, Claustre J, El Homsi M, Garzon J, Jourdan G, et al. beta-
Casomorphin-7 regulates the secretion and expression of gastrointestinal mucins through a muopioid pathway. Am J Physiol Gastrointest Liver Physiol. 2006; 290(6): G1105-13.
5.
Nelson CJ, Schneider GM, Lysle DT. Involvement of central mu- but not delta- or kappa-
opioid receptors in immunomodulation. Brain Behav Immun. 2000; 14(3): 170-84.
6.
Ninkovic J, Roy S. Role of the mu-opioid receptor in opioid modulation of immune
function. Amino Acids. 2011.
7.
Boom M, Niesters M, Sarton E, Aarts L, Smith TW, Dahan A. Non-analgesic effects of
opioids: opioid-induced respiratory depression. Curr Pharm Des. 2012; 18(37): 5994–6004.
8.
Becker A, Hempel G, Grecksch G, Matthies H. Effects of beta-casomorphin derivatives
on gastrointestinal transit in mice. Biomed Biochim Acta. 1990; 49(11): 1203-7.
9.
Defilippi C, Gomez E, Charlin V, Silva C. Inhibition of small intestinal motility by casein: a
role of beta casomorphins? Nutrition. 1995; 11(6): 751-4.
10.
Mihatsch WA, Franz AR, Kuhnt B, Hogel J, Pohlandt F. Hydrolysis of casein accelerates
gastrointestinal transit via reduction of opioid receptor agonists released from casein in rats. Biol
Neonate. 2005; 87(3): 160-3.
11.
Schulte-Frohlinde E, Schmid R, Brantl V, Schusdziarra V. Effect of bovine β-
casomorphin-4-amide on gastrointestinal transit and pancreatic endocrine function in man. In:
Brantl V, Teschemacher H, editors. b-casomorphins and related peptides: recent developments.
New York: VCH Weinheim; 1994. p. 155-60.
12.
Daniel H, Vohwinkel M, Rehner G. Effect of casein and beta-casomorphins on
gastrointestinal motility in rats. J Nutr. 1990; 120(3): 252-7.
13.
Alhan E. The effect of naloxone in the prevention of experimental stress ulcers in rats. Z
Gastroenterol. 1990; 28(3): 139-41.
14.
Ho MM, Ogle CW, Dai S. Morphine enhances gastric mucus synthesis in rats. Eur J
Pharmacol. 1986; 122(1): 81-6.
15.
Allen A, Flemstrom G, Garner A, Kivilaakso E. Gastroduodenal mucosal protection.
Physiol Rev. 1993; 73(4): 823-57.
16.
Claustre J, Toumi F, Trompette A, Jourdan G, Guignard H, Chayvialle JA, et al. Effects of
peptides derived from dietary proteins on mucus secretion in rat jejunum. Am J Physiol
Gastrointest Liver Physiol. 2002; 283(3): G521-8.
17.
Trompette A, Claustre J, Caillon F, Jourdan G, Chayvialle JA, Plaisancie P. Milk bioactive
peptides and beta-casomorphins induce mucus release in rat jejunum. J Nutr. 2003; 133(11):
3499-503.
18.
Hansson GC. Role of mucus layers in gut infection and inflammation. Curr Opin
Microbiol. 2012; 15(1): 57-62.
19.
Lai SK, Wang YY, Hanes J. Mucus-penetrating nanoparticles for drug and gene delivery
to mucosal tissues. Adv Drug Deliv Rev. 2009; 61(2): 158-71.
20.
Harrison OJ, Maloy KJ. Innate immune activation in intestinal homeostasis. J Innate
Immun. 2011; 3(6): 585-93.
21.
MacDonald TT, Monteleone I, Fantini MC, Monteleone G. Regulation of homeostasis
and inflammation in the intestine. Gastroenterology. 2011; 140(6): 1768-75.
22.
Kim JS, Sampson HA. Food allergy: a glimpse into the inner workings of gut
immunology. Curr Opin Gastroenterol. 2012; 28(2): 99-103.
23.
Elitsur Y, Luk GD. Beta-casomorphin (BCM) and human colonic lamina propria
lymphocyte proliferation. Clin Exp Immunol. 1991; 85(3): 493-7.
24.
Kayser H, Meisel H. Stimulation of human peripheral blood lymphocytes by bioactive
peptides derived from bovine milk proteins. FEBS Lett. 1996; 383(1-2): 18-20.
25.
Montalto M, Santoro L, D'Onofrio F, Curigliano V, Gallo A, Visca D, et al. Adverse
reactions to food: allergies and intolerances. Dig Dis. 2008; 26(2): 96-103.
26.
Hoffman L. A2 milk stands out from the herd (May 17, 2008). Available from: http://
www.theaustralian.com.au/news/health-science/a2-milk-stands-out-from-the-herd/storye6frg8y6-1111116350894
27.
Hammond G. Milk minus mutants boost for the lactose intolerant (July 16, 2011).
Available from: http://www.heraldsun.com.au/news/milk-minus-mutants-boost-for-the-lactoseintolerant/story-e6frf7jo-1226096018913
28.
Migliore-Samour D, Floc'h F, Jolles P. Biologically active casein peptides implicated in
immunomodulation. J Dairy Res. 1989; 56(3): 357-62.
29.
Migliore-Samour D, Jolles P. Casein, a prohormone with an immunomodulating role for
the newborn? Experientia. 1988; 44(3): 188-93.
30.
Kurek M, Przybilla B, Hermann K, Ring J. A naturally occurring opioid peptide from cow's
milk, beta-casomorphine-7, is a direct histamine releaser in man. Int Arch Allergy Immunol.
1992; 97(2): 115-20.
31.
Stępnik M, Kurek M. The influence of bovine casein-derived exorphins on mast cells in
rodents. Revue Française d'Allergologie et d'Immunologie Clinique. 2002; 42(5): 447-53.
32.
Kurek M, Czerwionka-Szaflarska M, Doroszewska G. Pseudoallergic skin reactions to
opiate sequences of bovine casein in healthy children. Rocz Akad Med Bialymst. 1995; 40(3):
480-5.
33.
Roy S, Wang J, Kelschenbach J, Koodie L, Martin J. Modulation of immune function by
morphine: implications for susceptibility to infection. J Neuroimmune Pharmacol. 2006; 1(1):
77-89.
34.
Sun Z, Zhang Z, Wang X, Cade R, Elmir Z, Fregly M. Relation of beta-casomorphin to
apnea in sudden infant death syndrome. Peptides. 2003; 24(6): 937-43.
35.
Wasilewska J, Sienkiewicz-Szlapka E, Kuzbida E, Jarmolowska B, Kaczmarski M,
Kostyra E. The exogenous opioid peptides and DPPIV serum activity in infants with apnoea
expressed as apparent life threatening events (ALTE). Neuropeptides. 2011; 45(3): 189-95.
36.
Lambeir AM, Durinx C, Scharpe S, De Meester I. Dipeptidyl-peptidase IV from bench to
bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP
IV. Crit Rev Clin Lab Sci. 2003; 40(3): 209-94.
37.
Sankaran K, Hindmarsh KW, Wallace SM, McKay RJ, O'Donnell M. Cerebrospinal fluid
and plasma beta-endorphin concentrations in prolonged infant apnea (near-miss sudden infant
death syndrome). Dev Pharmacol Ther. 1986; 9(4): 224-30.
38.
Storm H, Reichelt CL, Rognum TO. Beta-endorphin, human caseomorphin and bovine
caseomorphin immunoreactivity in CSF in sudden infant death syndrome and controls. Prog
Clin Biol Res. 1990; 328: 327-30.
39.
Wasilewska J, Kaczmarski M, Kostyra E, Iwan M. Cow's-milk-induced infant apnoea with
increased serum content of bovine beta-casomorphin-5. J Pediatr Gastroenterol Nutr. 2011;
52(6): 772-5.
40.
Hedner J, Hedner T. beta-Casomorphins induce apnea and irregular breathing in adult
rats and newborn rabbits. Life Sci. 1987; 41(20): 2303-12.
More in this series
•
•
•
BIOLOGY AND POTENTIAL EFFECTS OF A1
BETA-CASEIN-DERIVED BETA-CASOMORPHIN-7
BETA-CASEIN VARIANTS AND NEUROLOGICAL CONDITIONS
BETA-CASEIN PROTEINS AND INFANT GROWTH
AND DEVELOPMENT
Disclosure
This evidence-based report and others in the same series were developed by the medical
communications branch of Edanz Group Ltd (Hong Kong) to summarize key research findings
associated with bovine A1/A2 β-casein consumption. The reports were commissioned by A2
Corporation Ltd (Auckland, New Zealand).
BETA-CASEIN VARIANTS AND
NEUROLOGICAL CONDITIONS
BETA-CASEIN VARIANTS AND NEUROLOGICAL CONDITIONS
Executive summary
Consumption of cow’s milk protein, or more specifically the casein fraction, has been implicated
in modulating behaviour and aggravating symptoms associated with neurological conditions.1-3
Around 30% of cow’s milk protein is β-casein, of which there are two primary variants,
A1 and A2. Digestion of A1 β-casein (A1) yields the peptide β-casomorphin-7 (BCM-7), a widely
characterised exorphin, with the potential to be absorbed into the circulation and cross the
blood–brain barrier; A2 β-casein is not reported to yield BCM-7.
It is hypothesised that BCM-7 augments the behavioural symptoms of several
neurological diseases, including autism and schizophrenia, possibly via excessive activation of
opioid signalling pathways in the brain that have been characterised in vitro.
Research highlights
•
Digestion of A1 β-casein, but not that of A2 β-casein yields β-casomorphin-7 (BCM-7), an
exogenous opioid peptide (exorphin) that can potently activate opioid receptors in the
central nervous system
•
The serum/urine levels of casein, BCM-7, and antibodies to casein were reported to be
elevated in some people with neurological diseases, including autism and schizophrenia
•
A1 consumption, via BCM-7, may activate opioid signalling pathways in the central
nervous system to augment the behavioural symptoms of conditions including autism and
schizophrenia
•
In infants, consumption of cow’s milk formula and elevated blood BCM-7 levels were
associated with delayed psychomotor development and abnormally high muscle tone
•
A1-derived BCM-7 may induce oxidative stress by disrupting glutathione uptake or
oxidizing lipoproteins
•
Oxidative stress reduces methylation capacity and induces neurological deficits that are
associated with the symptoms of autism and schizophrenia
•
Consumption of a diet excluding A1 β-casein could help to avoid augmentation of the
behavioural symptoms of autism and schizophrenia, and prevent delays in psychomotor
development
Introduction
β-casein is a major protein expressed in human and cow’s milk and is present in many food
products derived from milk. In cow’s milk, two primary variants of β-casein, termed A1 and A2,
and several rarer sub-variants have been identified. A1 and A2 β-casein differ in their protein
structure by a substitution of the amino acid at position 67. A1 β-casein contains a histidine
residue at this position, which allows cleavage of the preceding seven amino acid residues to
yield the peptide β-casomorphin-7 (BCM-7). A2 β-casein contains a proline residue at this
position, which prevents cleavage of this peptide.4 The sub-variant B β-casein also has a
histidine at position 67, and its cleavage also results in the generation of BCM-7, but this variant
is much less frequent than A1 or A2 β-casein in the milk of cows of European origin.
BCM-7 has the potential to cross the gastrointestinal wall and the blood–brain barrier, so
it may influence peripheral and central systems. In fact, BCM-7 has been linked with several
neurological disorders, including autism,5 schizophrenia,1, 6 respiratory depression/apnoea,7, 8
and psychomotor development.9
Associations of β-casein with autism and schizophrenia
Autism spectrum disorders are principally associated with impaired social functioning and
communication, and limited flexibility of thought and behaviour.10 Several studies have reported
a link between casein and autism spectrum disorders, including elevated urinary peptide
secretion and the presence of antibodies to casein in individuals with autism.1, 2, 5, 11 However,
some studies have reported no such association.12 Associations between casein, particularly
antibodies to casein, and schizophrenia have also been reported.6, 13-16
Central effects of BCM-7 in autism and schizophrenia
These effects of casein augmenting the symptoms of autism and schizophrenia are most likely
attributable to exorphin activity in the brain.3 Indeed, it was reported that BCM-7, a product of A1
β-casein digestion, significantly reduced normal behaviours, such as rearing, walking and
grooming in rats, and enhanced abnormal activities, such as explosive motor behaviour, circling
and decreased social interaction (Figure 1).17 These behavioural effects of BCM-7 were caused
by its interaction with opioid receptors, as the effects were abolished by the specific opiatereceptor antagonist naloxone. BCM-7 also induced fos-like immunoreactivity in brain regions
relevant to schizophrenia, particularly the prefrontal cortex, the nucleus accumbens, the bed
nucleus of the stria terminalis, and the caudate–putamen.18
Figure 1. Behavioural effects of BCM-7 in rats. Drawn based on data presented in Sun and
Cade (1999).17 A, explosive motor behaviour; B, autonomic changes (pupil dilation, rapid
respiration); C, circling; D, reduced sound response; E, decreased social interaction; E,
abnormal feelings (biting or lipping feet or tail); F, hyperemotionality; G, catalepsy.
"
BCM-7 may also augment the symptoms of schizophrenia and autism by inducing
oxidative stress in the brain. In vitro, BCM-7 was reported to lower cellular levels of glutathione,
an antioxidant, by inhibiting cysteine uptake.19 β-casein can also promote low-density lipoprotein
(LDL) oxidation,20 which is normally associated with atherosclerosis. However, abnormal lipid
oxidation may also occur in the central nervous system, and may exacerbate the oxidative
environment in neurological disorders like schizophrenia.21 This oxidative environment can
result in impaired methylation of DNA and phospholipids, for example, and neurological deficits
that ultimately manifest as symptoms of schizophrenia and autism (Figure 2).22
Figure 2. A redox/methylation hypothesis for autism. Reprinted from Deth et al. (2008).22
"
BCM-7 and psychomotor development
BCM-7 may also affect other neurological activities, including psychomotor development. Kost
et al.9 reported that immunoreactivity of human and bovine BCM-7 could be detected in breastfed and formula-fed infants, respectively, within the first 3 months of life. Notably, elevated
bovine BCM-7 immunoreactivity was associated with delayed psychomotor development and
abnormally high muscle tone. By contrast, the opposite was found for human BCM-7, as infants
with the highest human BCM-7 immunoreactivity showed the best psychomotor development.
Further studies are needed to confirm these findings, and to evaluate the impact of diets aimed
at avoiding A1 β-casein.
Opportunities for managing autism, schizophrenia, and psychomotor
development
Several small-scale studies have demonstrated that switching to a gluten- and casein-free diet
may ameliorate some of the symptoms of autism,23-26 Considering the potential effects of
BCM-7, switching patients to a diet excluding A1 β-casein could help uncover causative factors
in autism spectrum disorders and schizophrenia. Current studies have focused on the removal
of gluten and casein from the diet; well-designed, prospective studies are needed to confirm the
specific clinical effects of A1 β-casein, and the benefits of replacing A1 β-casein with A2 βcasein to avoid augmenting the symptoms of autism and schizophrenia. Provision of breast milk
or cow’s milk formula lacking A1 β-casein may also help to prevent delays in psychomotor
development.
References
1.
Cade R, Privette M, Fregly M, Rowland N, Sun Z, Zele V, et al. Autism and
schizophrenia: intestinal disorders. Nutr Neurosci. 2000; 3: 57-72.
2.
Reichelt KL, Ekrem J, Scott H. Gluten, milk proteins and autism: dietary intervention
effects on behavior and peptide secretion. J Appl Nutr. 1990; 42: 1-11.
3.
Shattock P, Whiteley P. Biochemical aspects in autism spectrum disorders: updating the
opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin
Ther Targets. 2002; 6(2): 175-83.
4.
Jinsmaa Y, Yoshikawa M. Enzymatic release of neocasomorphin and beta-casomorphin
from bovine beta-casein. Peptides. 1999; 20(8): 957-62.
5.
Reichelt KL, Knivsberg AM. Can the pathophysiology of autism be explained by the
nature of the discovered urine peptides? Nutr Neurosci. 2003; 6(1): 19-28.
6.
Dohan FC. Genetic hypothesis of idiopathic schizophrenia: its exorphin connection.
Schizophr Bull. 1988; 14(4): 489-94.
7.
Sun Z, Zhang Z, Wang X, Cade R, Elmir Z, Fregly M. Relation of beta-casomorphin to
apnea in sudden infant death syndrome. Peptides. 2003; 24(6): 937-43.
8.
Wasilewska J, Sienkiewicz-Szlapka E, Kuzbida E, Jarmolowska B, Kaczmarski M,
Kostyra E. The exogenous opioid peptides and DPPIV serum activity in infants with apnoea
expressed as apparent life threatening events (ALTE). Neuropeptides. 2011; 45(3): 189-95.
9.
Kost NV, Sokolov OY, Kurasova OB, Dmitriev AD, Tarakanova JN, Gabaeva MV, et al.
Beta-casomorphins-7 in infants on different type of feeding and different levels of psychomotor
development. Peptides. 2009; 30(10): 1854-60.
10.
Wing L. The autistic spectrum. Lancet. 1997; 350(9093): 1761-6.
11.
Kawashti MI, Amin OR, Rowehy NG. Possible immunological disorders in autism:
concomitant autoimmunity and immune tolerance. Egypt J Immunol. 2006; 13(1): 99-104.
12.
Cass H, Gringras P, March J, McKendrick I, O'Hare AE, Owen L, et al. Absence of
urinary opioid peptides in children with autism. Arch Dis Child. 2008; 93(9): 745-50.
13.
Niebuhr DW, Li Y, Cowan DN, Weber NS, Fisher JA, Ford GM, et al. Association
between bovine casein antibody and new onset schizophrenia among US military personnel.
Schizophr Res. 2011; 128(1-3): 51-5.
14.
Reichelt KL, Landmark J. Specific IgA antibody increases in schizophrenia. Biol
Psychiatry. 1995; 37(6): 410-3.
15.
Severance EG, Dickerson FB, Halling M, Krivogorsky B, Haile L, Yang S, et al. Subunit
and whole molecule specificity of the anti-bovine casein immune response in recent onset
psychosis and schizophrenia. Schizophr Res. 2010; 118(1-3): 240-7.
16.
Severance EG, Lin J, Sampson HA, Gimenez G, Dickerson FB, Halling M, et al. Dietary
antigens, epitope recognition, and immune complex formation in recent onset psychosis and
long-term schizophrenia. Schizophr Res. 2011; 126(1-3): 43-50.
17.
Sun Z, Cade RJ. A peptide found in schizophrenia and autism causes behavioral
changes in rats. Autism. 1999; 3(1): 85-95.
18.
Sun Z, Cade RJ, Fregly MJ, Privette RM. β−casomorphin induces Fos-like
immunoreactivity in discrete brain regions relevant to schizophrenia and autism. Autism. 1999;
3(67-83).
19.
Trivedi MS, Hodgson N, Deth R. Morphine and gluten/casein derived opiate peptides
inhibit cysteine uptake and decrease glutathione: Implications for the Redox/ Methylation theory
of autism. International Meeting for Autism Research; 2010. p. Abstract 130.039 60.
20.
Torreilles J, Guerin MC. [Casein-derived peptides can promote human LDL oxidation by
a peroxidase-dependent and metal-independent process]. C R Seances Soc Biol Fil. 1995;
189(5): 933-42.
21.
Adibhatla RM, Hatcher JF. Lipid oxidation and peroxidation in CNS health and disease:
from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2010; 12(1):
125-69.
22.
Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M. How environmental and
genetic factors combine to cause autism: A redox/methylation hypothesis. Neurotoxicology.
2008; 29(1): 190-201.
23.
Elder JH, Shankar M, Shuster J, Theriaque D, Burns S, Sherrill L. The gluten-free,
casein-free diet in autism: results of a preliminary double blind clinical trial. J Autism Dev Disord.
2006; 36(3): 413-20.
24.
Knivsberg AM, Reichelt KL, Hoien T, Nodland M. A randomised, controlled study of
dietary intervention in autistic syndromes. Nutr Neurosci. 2002; 5(4): 251-61.
25.
Pennesi CM, Klein LC. Effectiveness of the gluten-free, casein-free diet for children
diagnosed with autism spectrum disorder: based on parental report. Nutr Neurosci. 2012; 15(2):
85-91.
26.
Sponheim E. [Gluten-free diet in infantile autism. A therapeutic trial]. Tidsskr Nor
Laegeforen. 1991; 111(6): 704-7.
More in this series
•
Beta-casein and digestive, respiratory and immune functions
•
Beta-casein and type 1 diabetes
•
Beta-casein and ischaemic heart disease/atherosclerosis
•
Biology and interactions of A1-derived β-casomorphin-7
•
Beta-casein and infant growth and development
Disclosure
This evidence-based report and others in the same series were developed by the medical
communications branch of Edanz Group Ltd (Hong Kong) to summarize key research findings
associated with bovine A1/A2 β-casein consumption. The reports were commissioned by A2
Corporation Ltd (Auckland, New Zealand).
BETA-CASEIN PROTEINS
AND INFANT GROWTH
AND DEVELOPMENT
BETA-CASEIN PROTEINS AND INFANT GROWTH AND DEVELOPMENT
Executive summary
While breast milk is recommended for infants, breast feeding may not be possible for medical or
personal reasons, in which case milk formula is used instead. Milk formula is usually based on
cow’s milk with the addition of essential nutrients and vitamins. A major protein component of
cow’s milk is β-casein comprising ~30% of total milk protein, of which there are two primary
variants, A1 and A2. Owing to subtle structural differences between these proteins, digestion of
A1, but not A2, yields the peptide β-casomorphin-7 (BCM-7), an exorphin that may interact with
a variety of body systems. A range of studies have linked A1 or BCM-7 to an increased risk of
type 1 diabetes in some infants, immune responses, digestive disorders, and respiratory
dysfunction. The A2 protein, which reportedly does not produce BCM-7, is more comparable to
the human β-casein protein, which accounts for >80% of the protein in mothers’ breast milk.
Therefore, a formula based on the A2 protein, excluding A1 protein, may more closely mimic
breast milk and may help to maintain optimal growth and development.
Research highlights
•
Breast milk is preferred, but may not be available for all infants, meaning a cow’s milkbased formula may be required
•
A major protein component of cow’s milk is β-casein, making up ~30% of total milk
protein. There are two major variants of β-casein, A1 and A2
•
Owing to a subtle structural difference, digestion of A1, but not A2, yields β-casomorphin7 (BCM-7), an exogenous opioid peptide (exorphin) that can potentially interact with a
variety of body systems
•
A2 is structurally more comparable than A1 to the β-casein protein in human breast milk,
which accounts for >80% of the total protein content
•
The immature digestive system of infants compared with that of adults increases the
likelihood of incomplete cleavage of A1 β-casein. This leads to production of BCM-7 and
its potential absorption into the blood stream and across the blood–brain barrier
•
Following its production in the digestive tract, BCM-7 can potentially impart adverse
effects on the digestive system or on other organs upon absorption into the systemic
circulation
•
A growing body of research has shown associations of A1 or BCM-7 with a range of
adverse effects, including increased risk of type 1 diabetes in some children, intolerance
reactions, and digestive disorders
•
More recent studies have reported correlations between the levels of BCM-7 derived from
A1-containing formulas in infants and both delays in psychomotor development and
respiratory dysfunction
•
Consumption of an infant formula containing only A2 β-casein, with the exclusion of A1,
may therefore help to maintain a range of functions in growing and developing infants
Introduction
Breast milk is the preferred source of nutrition for infants. The World Health Organization
recommend that infants should be exclusively breastfed for the first 6 months of life, and that
breastfeeding should be continued for up to 2 years or beyond together with appropriate solid
foods.1 However, not all infants can be breastfed, and some families may not have access to a
healthy wet-nurse or human milk-bank. In such situations, the family will need to use
commercial or home-prepared infant formula instead. Most infant formulas are produced from
cow’s milk, as it is a relatively cheap source of protein and nutrients, and is abundantly
available. However, the protein compositions of breast milk and cow’s milk differ substantially.
For example, breast milk is whey dominant, with an approximate casein to whey ratio of 40:60,
ranging from 10:90 in early lactation to 50:50 in late lactation. By contrast, cow’s milk and infant
formula have casein to whey ratios as high as 80:20.2
β-casein is a major protein expressed in human and cow’s milk and is present in many
food products derived from milk. In cow’s milk, two primary variants of β-casein, termed A1 and
A2, and several much rarer sub-variants have been identified. A1 and A2 β-casein differ in their
protein structure by a substitution of the amino acid at position 67 (Figure 1A). β-casein, like
other proteins, is an important source of amino acids and facilitates mineral transport, but can
be broken down into smaller bioactive peptides. A1 β-casein contains a histidine residue at this
position, which allows cleavage of the preceding seven amino acid residues, generating the
peptide β-casomorphin-7 (BCM-7). A2 β-casein contains a proline residue at this position, which
prevents cleavage of this peptide.3 The protein structure of β-casein in breast milk is similar to
that of A2 β-casein in cow’s milk (Figure 1B); therefore, human β-casein is not susceptible to
this mode of cleavage.
BCM-7 has a demonstrated potential to cross the gastrointestinal wall to enter the
systemic circulation and influence systemic and cellular activities via opioid receptors.
Moreover, BCM-7 and other derivatives of β-casein are potent exogenous agonists—
exorphins—for opioid receptors, with the greatest affinity for µ receptors.4 Consequently, BCM-7
has the potential to influence the activities of a variety of organs/systems, notably the digestive
system and immune cells, It may also be involved in various disorders in infants, including type
1 diabetes5 and respiratory dysfunction,6 and may influence central nervous system activity.7
Figure 1. (A) Cleavage of A1 β-casein at position 67 yields the peptide β-casomorphin-7. (B)
Sequence comparison of A1 and A2 β-casein in cow’s milk and the corresponding sequence in
human β-casein.
A
Tyr
A2 beta casein and related sub-­‐
variants release BCM-­‐9 preferentially
Pro
Phe
Pro
Gly
Pro
Ile
Pro
Asn
Amino Acid position 67 digestion
a2 beta casein
protein chain
Val
Tyr
Pro
Phe
Pro
Gly
Pro
Ile
Pro
Asn
Ser
Leu
Pro
a1 beta casein
protein chain
Val
Tyr
Pro Phe
Pro
Gly
Pro
Ile
His
Asn
Ser
Leu
Pro
BCM-­‐7 is reported as:
• Strong exogenous opioid
• A catalyst for oxLDL formation
Amino Acid position 67
digestion
A1 beta casein and related sub-­‐
variants release BCM-­‐7 preferentially
Tyr
Pro Phe
Pro
Gly
Pro
Ile
Adapted from: Gobbetti M, Stepaniak L, De Angelis M, Corsetti A, Di Cagno R. 2002 Latent bioactive peptides in milk proteins: proteolytic activation and significance in dairy processing. Crit Rev Food Sci Nutr. 42(3): 223-­‐39. & Jinsmaa, Y & Yoshikawa, M. 1999. Enzymatic release of neocasomorphin and beta-­‐casomorphin from bovine beta-­‐casein. Peptides 20(8): 957-­‐962.
B1
A1-derived BCM-7 and the digestive system
Andiran et al. reported that chronic constipation and the development of anal fistulas were
significantly associated with the volume of cow’s milk consumed and a shorter duration of breast
feeding in infants.8 This phenomenon may be related to the morphine-like effects of BCM-7.9, 10
The digestive tract of infants is very immature, particularly in terms of enzyme expression
profiles and commensal bacteria,11 undergoing continual development from birth to weaning.12
Because proteins are principally digested in the intestinal tract in infants, rather than in the
stomach as in adults, the likelihood of incomplete digestion of β-casein to amino acids is much
greater in infants. Furthermore, the neonatal gut is designed to absorb relatively large
macromolecules, particularly lactoglobulins, from breast milk. A consequence of these essential
features of the infant gut may include increased generation and uptake of BCM-7, which may
directly affect the functions of the digestive tract by slowing gastrointestinal transit, altering
mucus secretion, and may facilitate the development of anal fistulas. The protein fragments may
also have important roles in immunologic and allergic reactions.13
A1-derived BCM-7 and immune function
While the immunomodulatory effects of morphine are generally well established, the potential
immunomodulatory effects of β-casein and its cleaved peptides were first identified in the
1980s.14, 15 Since then, it has become apparent that exorphins, including BCM-7, have
immunomodulatory properties. For example, BCM-7 was reported to trigger histamine release
from peripheral leukocytes 16 and to have secretagogue effects on peritoneal mast cells.17
Studies have shown that BCM-7 alters lymphocyte proliferation in vitro through a pathway
mediated by opiate receptors.18, 19 The first of these studies showed suppressive effects of
BCM-7 on lymphocyte proliferation at all concentrations tested,18 while the second study
showed suppressive effects of low BCM-7 doses and stimulatory effects at higher doses.19
Clinically, BCM-7 may induce allergic reactions by stimulating excessive histamine
release, which may lead to localised pseudoallergic skin reactions or airway inflammation.16, 20
Impaired immune function may also increase susceptibility to infection and other potentially
severe diseases, as has been reported for morphine.21 Although additional studies are needed
to establish the specific immunomodulatory effects of BCM-7 and related peptides, and to
determine their clinical implications, these adverse events could be avoided by excluding A1 βcasein from the diet.
A1 β-casein and type 1 diabetes
Type 1 diabetes is characterised by autoimmune-mediated destruction of pancreatic β cells. Its
incidence is progressively increasing in many countries.22, 23 One explanation for this is that
environmental factors play major roles in its pathogenesis.24
A link between cow’s milk and type 1 diabetes in animals was first reported in 198425; a
link to type 1 diabetes in humans was first reported in 1990.26 A subsequent study proposed that
early exposure to cow’s milk may increase the risk of type 1 diabetes by approximately 1.5
times.27 Since then, several published studies have supported this association,28-30 although
other studies have found no association between antibodies to cow’s milk and the risk of type 1
diabetes.31-33
The identification of A1 and A2 β-casein, and the increased understanding of their
differing effects on immune function, prompted the hypothesis that the discrepancies in
epidemiological findings may be, at least partly, attributable to the main type of β-casein
consumed in each country. In 1999, in an analysis of children aged 0–14 across 10
countries/regions, Elliott et al. reported that, while total cow’s milk protein consumption was not
significantly correlated with the incidence of type 1 diabetes (r = 0.402), the consumption of A1
β-casein was (r = 0.726).34 These findings were confirmed by two other independent studies
involving a larger number of countries/regions (Figure 2).35, 36 A study published in 2006
provided further support for the diabetogenic effects of A1 β-casein.37
Figure 2. Correlation between A1 β-casein supply per capita in 1990 and incidence of type 1
diabetes (1990–1994) in children aged 0–14 years in 19 countries. r = 0.92 (95% confidence
interval: 0.72–0.97; p < 0.0001). Dotted lines are the 95% confidence limits of the regression
line. Reprinted from Laugesen and Elliott (2003).35
To better understand the relationship between A1 β-casein and risk of diabetes, Birgisdottir et
al. compared the risk of type 1 diabetes among children and adolescents in Iceland and
Scandinavia.37 They found a significant correlation between the calculated consumption of A1 βcasein among 2-year-old children with the incidence of type 1 diabetes at the age of 0–14 years
(r = 0.9, P = 0.037). On the other hand, A1 β-casein consumption among 11–14-year-old
individuals was not associated with the incidence of type 1 diabetes. Their data also suggested
that the lower consumption of A1 β-casein from cow’s milk was a contributor to the lower
incidence of type 1 diabetes in Iceland than in Scandinavia. Therefore, avoiding the
consumption of A1 β-casein may reduce the risk of developing type 1 diabetes in adolescence.
A1-derived BCM-7 and respiratory function
Peptides derived from casein, including BCM-7, have been implicated in the aetiology of sudden
infant death syndrome.6 For example, Wasilewska et al. noted that infants with apparent life-
threatening events had higher serum levels of BCM-7 after apnoea compared with healthy
infants of the same age.38 Similar findings were reported for other BCMs and β-endorphins.39-41
Hedner and Hedner noted that BCMs can readily cross the blood–brain barrier in newborn
rabbits and cause dose-related depressions of respiratory frequency and tidal volume.42 They
found that BCM-7 was equipotent to morphine, and its effects were reversed or prevented by
naloxone, a µ-receptor antagonist.
A2 protein and avoidance of A1 may be a more natural alternative to A1 cow’s
milk
Based on the information accumulated to date, it would appear that consumption of dairy
products containing predominantly A1 β-casein may be associated with some adverse clinical
outcomes in some susceptible infants and young children, including digestive disorders,
immune disorders, type 1 diabetes, and respiratory dysfunction. By contrast, infants who are
mainly given breast milk, which contains β-casein that is more comparable in terms of structure
and digestion patterns to A2 than to A1 β-casein in cow’s milk, are at a lower risk of developing
these disorders. For infants requiring milk formula because of limited availability of breast milk,
the data published to date indicate that milk formula (or dairy products in older children) lacking
A1 β-casein may help to avoid a range of adverse effects or reactions.
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More in this series
•
•
•
BIOLOGY AND POTENTIAL EFFECTS OF A1
BETA-CASEIN-DERIVED BETA-CASOMORPHIN-7
BETA-CASEIN AND DIGESTIVE, RESPIRATORY,
AND IMMUNE FUNCTIONS
BETA-CASEIN VARIANTS AND NEUROLOGICAL
CONDITIONS
Disclosure
This evidence-based report and others in the same series were developed by the medical
communications branch of Edanz Group Ltd (Hong Kong) to summarize key research findings
associated with bovine A1/A2 β-casein consumption. The reports were commissioned by A2
Corporation Ltd (Auckland, New Zealand).