Why A2 Milk in the UK?

Transcription

1 BANT Featured Article Why A2 Milk in the UK? Sue McGarrigle is Technical Advisor for Bionutri and provides training and seminar programmes for CAM practitioners of all disciplines. She lectures to a variety of groups at national conferences, BANT groups and College and University students. Sue writes extensively, is a published author and has contributed to several healthcare publications. Sue McGarrigle - ND, DipION, NTCC, CNHC Registered, MBANT It is unusual that I am writing an article about the use of cows milk, particularly as many of us agree in essence that it should not be part of the adult diet; genetically speaking, the human body was not designed to drink milk after the weaning period. The first milk users are not thought to have been milk drinkers; (National Geographic August ) the utilisation of milk came from natural fermentation processes used to preserve food which led to the development of butter, cheese and yogurt about the time early man moved away from a hunter-gatherer society into an agricultural and community based society. Fermentation became popular at the dawn of civilization not only because it preserved food, but also because it provided a variety of tastes and food forms with unique nutrient complexes, the abundant microorganisms in the fermentation process producing vitamins, enzymes, antioxidants, beta-glucans and phytonutrients.(1) Fermented foods are now for many people a vital missing link in today s diet and with the advent of refrigeration this has negated our need to ferment milk so it can be utilised as an important nutritional and anti-microbial food. Here in the UK abundant supplies of pasteurised, homogenised bovine milk and other dairy products are a staple of our daily diet at all ages and we are the only species drinking another species fresh milk. For many people in the UK population, milk, particularly A1 betacasein dominant milk mainly from British Friesian cows, is now so entrenched into our daily nutritional intake that when problematic, trying to eliminate it or find suitable quality alternatives has been difficult in many past cases, along with good compliance. Adults frequently mistake gastrointestinal symptoms as a sign that they may have lactose intolerance or are unable to digest dairy products at all without knowing why. But there are aspects to milk digestion that I have found many practitioners and members of the public are not aware of including A1 milk protein intolerance so a solution may be not to impose restrictions on dairy, but to consume milk containing only A2 beta-casein and this article will focus on the potential health benefits of A2 rather than A1 milk inclusion in the diet. Lactose Intolerance Kefir an example of a fermented milk product Before we get into the growing body of research behind A2 Milk I am first going to talk about lactose intolerance as this is a common food intolerance associated with drinking milk that needs to be set apart. page 1

2 Nature has evolved for most babies to have the natural ability to digest their primary food i.e. breast or formula milk and produce adequate levels of lactase an enzyme that catalyzes hydrolysis of lactose into glucose and galactose in their digestive system with some exceptions; an example being premature babies who may have transient lactase deficiency which lasts temporarily and may lead to colicky type symptoms in the first few weeks of life. Infants of every racial and ethnic group worldwide produce lactase, however, sometime after weaning, in the majority of the world s children, there is a genetically programmed decrease in lactase (lactase nonpersisters).(2)today in most cultures the world over, adults do not drink milk and regardless they do not need the lactase enzyme. In some human populations lactase persistence has evolved as an adaptation to the consumption of non-human milk and dairy products beyond infancy. (3) The ability to digest lactose into adulthood (lactase persistence) would have only been useful to humans after the invention of animal husbandry and the domestication of animal species that could provide a consistent source of milk. Hunter-gatherer populations before the Neolithic revolution were overwhelmingly lactose intolerant, as are modern hunter-gatherers. (4, 5) Genetic studies suggest that the oldest mutations associated with lactase persistence only reached appreciable levels in human populations in the last ten thousand years. (6, 7) Therefore lactase persistence is often cited as an example of both recent human evolution (8, 9) and, as lactase persistence is a genetic trait but animal husbandry a cultural trait, gene-culture coevolution in the mutual human-animal symbiosis initiated with the advent of agriculture. (10) It has been determined that this continued genetic expression of lactase enzyme, (lactase persistence), is dependent on ancestry and racial background. Lactase persistence through natural selection is found at moderate to high frequencies in Europeans and some African, Middle Eastern and Southern Asian populations (11) and this was a strong evolutionary advantage for people able to consume milk and its nutrients without digestive discomfort, in order to survive and, when the alternative was contaminated water. The majorities of people around the world remain lactase nonpersistent (12) and consequently are affected by varying degrees of lactose intolerance as adults though not all genetically lactase non-persistent individuals are noticeably lactose intolerant and not all lactose intolerant individuals have the lactase non-persistence allele. In the UK, around five in 100 people have lactose intolerance. (BUPA 2013) Lactose intolerance (which is not a milk allergy- the definition being an immune reaction to one or more proteins in milk) has been defined as symptoms developing after ingestion of lactose which do not develop after placebo challenge in a person with lactose maldigestion. Lactose intolerance has been reported to cause uncomfortable reactions in the digestive tract and apart from having a genetically determined characteristic may have a secondary cause, such as gastro-enteritis or chemotherapy. The lactose-rich diet in Western countries can cause symptoms in individuals with the lactase non-persistence phenotype. If diagnosed correctly symptoms are caused by the undigested lactose in the gut after ingestion of lactose containing foods and may include abdominal bloating and cramps, flatulence, diarrhoea, nausea, borborygmi (rumbling stomach), or vomiting after consuming significant amounts of lactose. (13) Lactose malabsorption refers to inefficient digestion of lactose due to reduced expression or impaired activity of the enzyme lactase. Studies have shown however that even diagnosed lactose malabsorbers are capable of consuming moderate amounts of dairy, tolerating an average 12 grams of lactose when administered in a single dose (the lactose content found in 1 cup of milk) with little to no symptoms. (14) Additionally, many adults who believe they have lactose intolerance are actually suffering from other gastrointestinal disorders such as SIBO, yeast overgrowth, coeliac disease, or Irritable Bowel Syndrome, and do not see significant benefit from eliminating dairy. In addition, not all foods with milk in them will cause problems. For example, lactose is broken down by fermentation processes and is not found in hard cheese such as cheddar or emmenthal. (15) For individuals who wish to improve their digestive health the use of probiotic bacteria found in fermented foods such as cottage cheese and yogurt, which can metabolise lactose for energy, can have significant benefits. Examples of popular lactic acid bacteria such as L.kefir, L.acidophilus, L.bulgaricus, L.casei, B.longum and B.lactis can improve symptoms of/and lactose digestion and tolerance. (16, 17) More significantly a proportion of adults who report milk intolerance symptoms, lactose intolerance may not be the cause, as cases of perceived lactose intolerance are more common than its prevalence in adults. In a group of 406 randomly recruited men and women 20.2% reported abdominal discomfort following dairy intake, but only 6.4% of those had lactose intolerance diagnosed by a physician. (18) Studies show about 20 per cent of British consumers do not drink milk, but only 5-6 per cent are clinically proven to be lactose intolerant. In these cases, A2 milk, free from A1 protein, could potentially enable them to drink milk again. (19) Difference between bovine and human milk As the primary source of food we are raised on and beyond, milk s chemical and physical structure varies considerably between species. There are considerable insights to be gained by comparing bovine milk to human milk. As a starting point, it is a fairly safe assumption that if there are problems associated with bovine milk then they will be because of components that are present in bovine milk but absent from human milk or, alternatively, because the balance between components is substantially different between the two. Bovine and human milk solids differ, casein being much higher in cows milk (80:20 ratio), but the liquid whey is more dominant in human milk (90:10 in colostrum, 60:40 in mature milk and 50:50 in late milk), human milk is higher in lactose, similar in fat but much lower in protein. It is also considerably lower in minerals so it can be iso-osmotic with blood in the mammary gland. (19) The major proteins in human milk are whey whereas the higher protein content in cows is mainly casein. Bovine caseins are confirmed as alphas1, alphas2, beta, and kappa-casein.(20) It is the beta-caseins that are the main focus of attention for human health. page 2

3 Beta-casein content and potential BCM-7 release per 250mL of milk. Although beta casein is the most important of the human casein proteins, it is different to the beta casein produced by cows having a shorter protein chain. There are two primary forms of beta-casein contained in cow s milk, A1 beta-casein and A2 beta-casein, in human milk all beta casein is of the A2 type. (19) A1 beta casein is a string of 209 amino acids that comprises 30% of the protein contained in cows milk and very closely resembles the other milk protein A2 beta casein. A2 beta-casein is the beta-casein form cows have produced since before they were first domesticated, over 10,000 years ago. It is considered safe and nutritious and has no known negative effects on human health. Sheep and goats also produce A2 milk. Sometime in the past few thousand years, a natural mutation occurred in some European dairy herds that changed the betacasein they produced. The gene encoding beta-casein was changed such that the 67th amino acid in the 209 amino acid chain that is the beta-casein protein was switched from proline to histidine. (A2 Corporation) A1 and A2 beta-casein proteins showing the amino acid difference at position 67. This difference can be detected easily by a noninvasive DNA test that indicates accurately which beta-casein genes a cow carries. This new kind of beta-casein that was created is known as A1 beta-casein, and is generally more common in many of the big black-and-white cow breeds of European descent such as the Holstein and Friesian. It is likely that the A1 allele became common not through selection due to any specific advantage but more due to what animal breeding specialists call the founder effect. The founder effect is about the very large impact of the genetic profile of the individual animal from which the breed was founded. Due to their size, milk production, and demeanour, Holstein/Friesian breeds of cow are used to produce the vast majority of Northern Europe and America s milk, some 75% of the world s 300 million strong dairy herds produce milk that contains the protein beta casein A1. (World Guernsey Cattle Federation,19) Photo courtesy British Friesian breeds originate in Western Europe, in particular Holland and North Germany. The British Friesian became established in the UK during the Nineteenth Century, particularly in the eastern and home counties and southern Scotland. The first Herd Book was founded in The Holstein, as we know today, was first established in North America starting with an imported bull and four heifers from Holland into the United States in the 1850s. The breed first appeared in the UK in the years immediately after the Second World War, during which time around 2000 in-calf heifers, plus a few bulls and cows, were imported from Canada in conjunction with shiploads of store cattle. (Holstein UK) Cows in the well-known dairy breeds, including the Guernsey, can produce either or both of the bovine beta casein proteins. They can be A1/A1, A1/A2, or A2/A2. Research has shown that about 96% of Guernsey cows produce only beta casein A2 (World Guernsey Cattle Federation), which is interesting because I have been following the rise in popularity of A2 milk, and this all started when my interest was certainly piqued several years ago when it came to my attention that a very small, private trial had been initiated in a school on the east coast of England. 50 children on the autistic spectrum had been offered A2 milk and yogurt from Guernsey cow s with some surprising and very positive results i.e. not the usual reactions that you would expect when compared to ingestion of A1 milk. Since then I have been tracking the research surrounding A2 bovine milk that has been published and discovered some very interesting facts. Proteins are a very diverse family of large organic compounds involved in many important biological processes. Following their enzymatic hydrolysis during food processing or digestion, proteins may release fragments from their primary amino acid sequence. These fragments are called peptides, and many of them are page 3

4 known to be physiologically active. The possible beneficial effects of bioactive peptides have attracted increasing interest in recent years. On the other hand, there are also reports suggesting that some food-derived peptides might adversely affect human health. Opioid peptides play a role in various biological processes including respiration, analgesia, constipation and behaviour. (21) However, as noted by Maklakova et al. (1993), Depending on the type of peptide, the mode of its administration into the organism, the species of experimental animal, and the peptide dose, it is possible to register an entire spectrum of effects, ranging from significant motor excitation to a complete inhibition of locomotor activity and catotonia There is a somewhat controversial claim, backed by several years of research, that a component of beta-casein in A1 milk, which is drunk by most people in the western world, could be a cause of diabetes, heart disease, autism and schizophrenia in people with immune deficiencies. It is also claimed that A2 milk is benign in this respect. However, the argument most strongly advanced by the proponents of the benefits of A2 Milk is not that A1 Milk causes these illnesses but rather that A1 milk is digested in a different way to A2 resulting in the release of a peptide or protein fragment from the milk protein beta-casein called Beta-Casomorphin-7(BCM-7), which if it gets through the gut and into the blood of genetically susceptible people can have a detrimental effect by exacerbating underlying problems.(19)bovine BCM-7 is not the only opioid that can be produced in milk. BCM-7 and even more so BCM-5 that in some situations can be formed from it, are by far the strongest. Internal differences mean bovine BCM-7 is 10 xs more potent than the theoretical human equivalent. (22, 23)There are also opioid antagonists in milk that can to a larger extent negate the effect of the weaker opioids. (World Guernsey Cattle Federation, 19, 24) How is Beta-Casomorphin-7 (BCM-7) formed The difference between the A1 and A2 beta caseins of just a single amino acid sounds like a minor difference, but is quite significant because the bond between histidine and its adjacent amino acid in A1 beta casein is much weaker and much more easily broken than the bonding of proline in A2 beta casein. (19) Detailing this cause for concern with milk containing A1 betacasein is that the 67th amino acid switch from proline to histidine readily allows a digestive enzyme to cut out a 7 amino acid segment of the protein immediately adjacent to that histidine. When proline is present in that location (as it is in A2 beta-casein), that same segment is either not separated at all or the separation occurs at a very low rate. The 7 amino acid segment that is separated from A1 beta casein is BCM-7, is an exogenous opioid that can bind opioid receptors expressed in digestive, immune and neural tissue. (25) Comparison between A1, A2 and human beta-casein structures BCM-7 has Potential to Affect a Range of Tissues-Dr A J Clarke Dr S Kukuljan What about ingestion of other dairy products? There is a variety of heat methods used in pasteurisation and dependent on this they have the potential to break down and denature proteins. It is unclear as the protein structure breaks down which peptides are released and more BCM-7 may be released upon subsequent digestion than occurs when using intermediate temperature methods. When making ice cream A1 milk may be heated to high temperature to help mixing with other ingredients and has been known to cause reactions. Small amounts of BCM-7 may be found in cheese but this varies from cheese to cheese and may be negligible. It is unclear how much BCM-7 may be released during digestion as beta-casein in two of Britain s most popular cheeses is still intact at 63% for cheddar and 69% for mozzarella. Regarding intolerance the issue is further clouded by people who can t drink A1 milk but can tolerate A2 milk and can also tolerate small amounts of cheese but this may be due to the low amount of lactose contained in cheese. The cheese making process might render BCM-7 inactive but if there were very small quantities of BCM-7 this may not affect healthy individuals but may affect individuals with leaky gut. (19) Absorption of BCM-7 In healthy adults it should be difficult for BCM-7 as a large molecule to get through the gut wall and into the bloodstream, there is no simple answer as to the outcome because it does depend on the age, health and genetic make-up of the individual. Cleavage of BCM-7 page 4

5 With people who do suffer from leaky gut syndrome, BCM-7 and other peptides may pass easily into the bloodstream and BCM-7 may be detected in the urine. New-born babies may be susceptible as they need to be able to pass large molecules through the gut wall i.e. to absorb colostrum from their mother s milk. Other groups of individuals who may be susceptible are undiagnosed coeliac sufferers and individuals on the autistic spectrum. Evidence has been published that once BCM-7 has entered the bloodstream it crosses the blood brain barrier and attaches there to opioid receptors. (19, 26, 27, 28) Rodent studies have shown that intracarotid injection with BCMs results in their accumulation in blood-brain barrier-free and blood-brain barrier-protected areas. (29) I am going to summarise some of the main findings for various conditions (see below) but there is a great deal of research and evidence for the various pathologies and complex interactions involving BCM-7. If you want to explore this in far more depth I would recommend reading Devil in the Milk by Professor Keith Woodford who looks at the illness, health and politics of A1 and A2 milk. I would also recommend the website betacasein.org as a good source of the research that has been carried out. A Short Summary of Research Digestive system Bovine BCM-7 when released in the gut can affect the digestive system and like other opioids can reduce the rate of passage through the gut, causing constipation. (30, 31, 32, 33) BCMs are mu-type opioid agonists and mu-receptor activation is known to produce constipation. Zogbhi et al. (2006) examined the in vitro effects of BCM-7 on human colon goblet-like cells (HT29-MTX cells) and found that BCM-7 increased mrna levels of the mucin MUC5AC (219% after 24 hours of stimulation) and the secretion of this mucin (169% of controls), dependent on muopioid receptor activation. Notably, mucous owes its hydrophilic and viscoelastic properties to secretory mucins and MUC5AC is also one of the two main mucins produced in the respiratory tract. However, more research is needed to confirm BCM-mediated intestinal motility effects in humans. (34-42) This might explain why babies fed on formula milk rather than human milk are susceptible to constipation. BCM-7 may also increase problems of lactose intolerance as transit is slow with more fermentation occurring. BCM-7 has been shown to increase inflammatory activity of colonic immune cells and mucous production and thickening in the rat small intestine. (43) Researchers are now looking at the potential role BCM-7 may have in Ulcerative Colitis, Crohns disease and other autoimmune conditions and neurodegenerative conditions such as Multiple Sclerosis and Parkinsons Disease. (19) Infants Human BCM-7 has been identified in human breast milk and other human beta-casomorphins have been found in the blood of pregnant and lactating women but not in men or non-pregnant women, leading researchers to suggest that BCM-type mammary products have physiological significance during pregnancy or after parturition. (44, 45) Elevated circulating human BCM-7 has been correlated with beneficial developmental outcomes in breast fed infants, while the opposite has been observed in their bovine milk containing formula-fed counterparts with similarly elevated levels of bovine BCM-7.(46) In addition, Jarmolowska et al. (2007) have further shown that human BCM-7 concentration in colostrum (produced in the first days of lactation) is 7 times higher than in human milk at 2 months of age, which suggests that a human infant s requirement for human BCM-7 is significantly lower at 2 months compared with the first few days of life and that exposure to the more potent bovine BCM-7 at around 2 months of age may be undesirable. This work is consistent with earlier animal studies that have shown that BCM-7 induces apnoea and irregular breathing in new-born rabbits and adult rats that is analogous to sudden infant death syndrome (SIDS) in humans. (47). But evidence has shown that there are possibly many factors that can contribute to SIDS. The latest research by a Polish research group further confirms the presence of BCM-7 in the blood of babies, and that BCM-7 may be a risk factor for apnoea (expressed as apparent life threatening events ), compared to a group of healthy infants. In the at-risk apnoea infants, blood BCM-7 levels were on average three times higher compared with the normal infants. (48) Recent Polish research also identifies that at-risk infants have low blood levels of DPP-IV, the enzyme that metabolises BCM- 7. In the at-risk babies, DPP-IV levels were 58% of those found in healthy babies. Furthermore, in the normal children, BCM-7 was positively associated with DPP-IV levels. This relationship is absent in the at-risk babies. The statistics associated with these findings are strong (i.e. p<0.001 in each case). Not surprisingly, the Polish researchers also found that BCM-7 levels were higher in babies fed formula which was high in casein, compared to those fed formula that was low in casein. However, it could be regarded as surprising that bovine BCM-7 was also found in the blood of 1-4 month babies who were breast fed. The suggestion by the researchers is that bovine BCM-7 from milk ingested by lactating mothers can be transferred directly to the mothers milk. (49) Heart Disease Evidence regarding the connection between A1 and Heart Disease includes Epidemiology, animal studies and infant observational studies. Professor Eliot s work on the relationship between A1 milk and Type I diabetes (88) (see Diabetes section) was reviewed by Corann McLachlan, who then identified similar relationships across countries between intake of A1 milk and incidence of heart disease. Countries such as Iceland, where the milk is mainly A2 have much lower heart disease levels than countries of similar ethnicity such as Finland where there are high intakes of A1 milk. In some countries such as Germany where there are considerable breed differences between regions (and hence different levels of A1 beta casein) there are corresponding regional differences in heart disease. In Japan, where A1 consumption is very low, heart disease is also very low despite Japanese being heavy smokers. (Smoking is usually considered a big risk factor). The Masai in Kenya drink very high levels of milk but have very low levels of heart disease; all of their milk is A2. (19) Major differences in CHD incidence between countries of the developed world show strong correlations between A1 betacasein intake and the incidence of heart disease. The reported correlation coefficient (r) for the relationship between A1 betacasein consumption and heart disease is 0.76 or higher which page 5

6 is significant. Neither total milk protein nor A2 beta-casein intake have been linked to heart disease incidence. (50, 51) A1 versus A2 beta-casein intake in participant background diets. Oxidation of LDL cholesterol is fundamental to the process whereby fatty plaques are laid down in artery walls, leading to heart disease. The effects of BCM-7 on heart disease may not just be from the oxidant activity but also from an opioid-related mechanism related to immune function. (19) Even though strong and significant relationships have been shown linking A1 beta-casein with heart disease; currently there is no proof that the statistical correlations prove causation with absolute certainty, there have been no definitive human trials which could be difficult as heart disease takes so long to develop and it is not known whether there may be involvement of other factors. It is interesting though that the incidence of heart disease in Guernsey where Guernsey cows yield A2 milk is lower than the UK. Coincidence? Autism and Schizophrenia 1990 A1 beta-casein supply (A1/capita) and 1995 ischemic heart disease, 20 countries (r=0.76, 95% CI: ). Dotted lines are the 95% confidence limits of the regression line (51) Other research in human infants conducted by a Czechoslovakia research group supports the idea that bovine BCM-7 may be an early contributor to heart disease later in life. Steinerova et al. (2004) have shown that formula fed infants (beta-casein containing formula) have elevated serum levels of antibodies to oxldl relative to breast fed babies. Given that BCM-7 has been shown to oxidise LDL in vitro, it is possible that the differences in oxidised LDL between the formula and breast fed babies are mediated via A1 beta-casein derived BCM-7. (52, 53) Professor Julie Campbell from the University of Queensland is a specialist in vascular heart disease. Her research team fed A1 milk and A2 milk to rabbits. The rabbits fed A1 milk had higher cholesterol levels than the rabbits fed A2 milk. Much more importantly, the A1 rabbits developed lesions and thickening on the artery walls. Professor Campbell s work was published in 2003 in the international medical journal Atherosclerosis (Tailford et al. 2003). The conclusions were that A1 milk is atherogenic (causes heart disease) and that A2 milk may have a protective effect. Particularly important (and worrying) is that the lesions in the arteries of rabbits fed A1 milk were very similar to what is known as juvenile fatty streaks in humans. This arterial damage was paralleled by a shift in the LDL: HDL ratio. (54) Trials in adult humans have investigated the differential effects of A1 versus A2 beta-casein consumption on parameters of heart disease (55, 56). Both trials were unable to detect any differential effects in serum cholesterol levels and clinical markers of heart disease risk over 6 to 12 weeks. However, this is not unexpected given the investigated parameters are not linked directly to known BCM-7 activities, namely the oxidation of LDL. In addition, these trials had small participant numbers, and while the incidence of systemic exposure to bovine BCM-7 remains unknown, it is likely to be low and low incidence conditions require large study numbers to detect differences between two treatments. Furthermore, neither of these trials confirmed the production and absorption of BCM-7 in the serum of volunteers, neither included washout periods prior to the intervention arms and both failed to control adequately for The Opioid Excess Theory describes the hypothesis that exogenous opioids from the incomplete digestion of gluten and casein proteins can be absorbed across the gut into circulation and become biologically active through opioid receptor binding and thereafter aggravate symptoms in those with neurological conditions. (56, 57, 58) Alternatively, exogenous opioids may affect the serotoninergic system and play a pathogenic role in the development of autism (59, 60) resulting from adverse gastrointestinal pathology and abnormalities in exorphin peptide chemistry and metabolism. To this end, gastrointestinal symptoms are reportedly common in children with autism (61-65) and in adults with other psychiatric conditions such as schizophrenia. (66, 67) Recent research in human infants highlights that there are indeed differences in the rate of exorphin peptide clearance between babies. (68, 69) Currently, the cause or causes of autism spectrum disorders remain unknown, although genetic factors play a key role. (70, 71,) However, new evidence from a study of 192 pairs of monozygotic and dizygotic twin s highlights that environmental triggers may also play a causative role in susceptible individuals. More specifically, Hallmayer et al. (2011) found that shared environmental factors accounted for 58% of ASD cases, whereas genetic factors could explain only 38%. (72) Early exposure to environmental modifiers may also contribute to variable expression of autism-related traits in some individuals. Bovine BCM-7 has been detected in the blood of human infants by two different research groups using immunoassay methods, and bovine BCM-7 has also been detected in the urine of children with autism spectrum disorders using mass spectrometry analysis. (59) Note: BCM-7 enters many areas of the brain linked to autism whereas similar peptides from gluten cannot access most of these areas. (19) Gluten & Casein Free (GFCF) diets have been reported to improve the symptoms of autism. (73) Effectiveness of the diet is avoidance of exposure to food derived opioids (e.g.: BCM-7). Investigations by teams led by Cade, Reichelt and Shattock in three different countries confirm this. Systemic oxidative stress and brain neuro-inflammation have been described in autistic subjects, in association with significantly lower plasma levels of the antioxidant glutathione (GSH). Trivedi et al (2012) focused on studying the effects of opioid and food page 6

7 derived opioid peptides with implications in autism spectrum disorders (ASD) and drug addiction, investigating the epigenetic changes and consequent gene expression changes under the influence of redox status of neurons. They tested the hypothesis that casein and gluten-derived peptides modulate cysteine uptake by EAAT in cultured human neuronal and intestinal epithelial cells via their effect on opiate receptors, and this action alters cysteine availability for GSH production. The levels of glutathione regulate the levels of S-adenosyl methionine (SAM) via the activity of methionine synthase enzyme. SAM is a methyl donor for more than 200 methylation reactions including DNA and Histone methylation. DNA methylation analysis indicated global epigenetic changes induced by these peptides. The findings provided mechanistic support for the association of GI inflammation with coeliac disease and autism spectrum disorders and provided a plausible rationale for a GFCF dietary intervention in treating these diseases. The current study also provides a rationale for the preferential use of human breast milk over bovine milk/milk formula for infants. Their acute inhibition of cysteine uptake was similar to the effect of morphine, but less extensive, and was completely blocked by the opiate antagonist naltrexone, confirming opiate receptor involvement. The bovine form of BCM-7 was more potent as compared to the human form in inhibiting cysteine uptake and altering thiol metabolite levels. High levels of antibodies to beta-casein were found in >90% children with autism and schizophrenia. Within 3 months, Gluten- Casein free diets resulted in improvements in most categories of the behaviours in 81% of autistic children. (74, 75) Bovine BCMs were about 10-fold more potent than human BCMs and that 10-fold the dose of naloxone (an opioid antagonist) was needed to inhibit the effect of bovine BCMs compared with morphine. (76) In experimental rats that were given an intranigral injection with bovine BCM-7 and other BCMs they exhibited behavioural tendencies similar to those of autism and schizophrenia which were reversed with administration of a morphine antagonist. The contralateral rotational behaviour increased in a dose-dependent manner (intensity and duration), depending on the location of the injection. (76, 77, 78, 79) What needs to be established is whether opioids from beta casein cause the syndromes of autism and schizophrenia or whether they are causing or exacerbating the symptoms. Diabetes The initial link between A1 milk and Type 1 (childhood) diabetes was made by Professor Bob Elliot at Auckland University, who noted that Samoan children living in Samoa did not get diabetes but that Samoan children in New Zealand did. Subsequently he and colleagues demonstrated very strong between-country correlations between intake of A1 milk and level of Type 1 diabetes. Although genetic factors play a key role in development of Type 1 diabetes mellitus (DM-1), environmental and nutritional factors are believed to be modifiers, as only ~5% or fewer subjects with genetic susceptibility to DM-1 develop the clinical disease. (80-82) A recent double-blind, randomised trial of the first nutritional primary prevention study for DM-1 (TRIGR-Trial to Reduce IDDI in Genetically at Risk-) has found that autoantibody development can be delayed by giving hydrolysed formula (rather than regular cow smilk formula) during the first 6 8 months in at-risk infants. (83) Several studies report that breast feeding is protective. (84-88) A range of studies in developed countries have found that most of the between-country differences in the incidence of DM-1 can be explained by intake levels of the specific milk protein variant A1 beta-casein, and that this is a much stronger explanatory factor than total milk protein consumption per se. (51, 89, 90, 91) Correlation of A1 beta-casein per capita (excluding cheese) in grams/day and new cases of DM-1 in 0 to 14-year olds between (r=0.92, 95% CI: ) (p<0.0001). Dotted lines are the 95% confidence limits of the regression line [adapted from reference. All are higher-income countries with European type lifestyles (51) There is also evidence from Finland that amongst genetically susceptible children (i.e. those who have an older sibling with Type 1 diabetes) there is a relationship between the amount of cow s milk that is drunk and the chance of getting diabetes. (19) It is hypothesised that BCM-7 s opioid characteristics might contribute to the impairment of the development of gut-associated immune tolerance in at risk individuals and as such it might act as an adjuvant in the autoimmune reaction involved in the destruction of beta-cells in prediabetic subjects. (24, 92, 93, 94) This is supported by the attenuation of A1 beta-casein s apparent diabetogenicity following the administration of the opioid antagonist naloxone. (95) Secondly the potential antigenic determination characteristic of beta-casein may lead to the autoimmune destruction of pancreatic beta-cells. (96, 97) There may be molecular mimicry between a sequence of the beta-casein protein and an epitope of the GLUT 2 transporter which may give rise to autoantibodies capable of targeting pancreatic beta-cells. (98) What has been established is the following: Digestion of A1 but not A2 beta casein yields BCM-7 BCM-7 has the potential to bind opioid receptors expressed in cells throughout the body, including digestive, immune and neurological BCM-7 has been observed to be produced, absorbed and circulated in some humans, particularly infants Emerging evidence links BCM-7 to adverse effects on infant page 7

8 development and health, and intolerance type reactions in adults The proportion and type of individuals susceptible to BCM-7 exposure needs to be determined A1 has been linked by numerous epidemiological studies and animal trials with an increased risk in the incidence of heart disease and type 1 diabetes Infants have a range of abilities to break down BCM-7 (and thereby prevent negative BCM-7 effects) Consumption of milk containing only the A2 type of beta casein at the exclusion of A1 avoids exposure and risk of adverse reaction associated with the A1 or derived fragment BCM-7 Important note: You may have noticed the use of Casein Tryptic Hydrolysate (CTH) by some supplement companies. To avoid confusion-cth is as1-casein (alphas1-casein) hydrolysed with trypsin which yields a-casozepine, a decapeptide, a polypeptide that consists of a chain of ten amino acids which acts as an anticonvulsant and anxiolytic molecule with benzodiazepine-like activity. When peptides isolated from CTH were examined for their affinity for the -amino-butyric acid (GABA) type A receptor, only one peptide, named a-casozepine, corresponding to the fragment from bovine as1-casein, expressed affinity for GABAA receptor. The GABAA receptor complex plays a major role in the pharmacology, neurochemistry and physiopathology of stress and anxiety. The physicochemical characteristics and the pharmacological action of a-casozepine leads to the hypothesis that this peptide might play a role, as an external ligand, in the regulation of the nervous system of the mammalian new-born and might be involved in the traditional calming properties attributed to milk. CTH has not been shown to be problematic in lactose intolerance or milk allergy sufferers. (99) From the Dairy Council Farmers do not fill their cows with growth hormones (this is illegal), and only use antibiotics to treat cows suffering from mastitis. The milk from cows treated in this way is not collected for public consumption. Regular testing of all milk supplies by the government, confirms that no antibiotic residues are present in retail milk. Interestingly raw milk doesn t have the same testing stipulations for antibiotics as pasteurised milk. Not all raw milk is tested. India After an international study highlighted the link between a protein in the milk produced by western breed of cows and a range of serious illnesses, the Indian Council of Medical Research is now conducting a systematic study on this aspect. Entire world dairy authorities have taken cognizance of the research first made public by New Zealand researchers in (The New Indian Express April 2013) Summary Science relating to beta-casein variants has been the focus of two regulatory body reviews: by the New Zealand Food Safety Authority (NZFSA) in 2004 (100), which focused primarily on epidemiological analyses and feeding trials and by the European Food Safety Authority (EFSA) in 2009 (51), which examined potential links between BCM-7 and noncommunicable diseases. The EFSA report acknowledged that BCM-7 is an opioid that could affect a range of cells and tissue, including the digestive and immune systems, but that further research is needed to determine a causal link between A1 beta-casein consumption and disease. However, subsequent to the EFSA report two independent research groups have detected bovine BCM-7 in the circulation of formula-fed infants (containing A1 beta-casein) (68, 69), evidence that was not considered by EFSA. The reality is that the consumption of milk is a way of life for British households and there is no doubt that it is very nutritious even though there are a loss of certain enzymes and beneficial bacteria during pasteurisation, there has been much debate about the pro s and con s for pasteurisation versus raw milk but there have been some interesting benefits shown regarding ingestion of dairy which is another story. We also live in northern climes; many diets lack a wide variety and particularly leafy green vegetables and dairy foods are a cheap source of food for those on low incomes. Dairy from grass fed cows is also the primary source of the natural trans-fat conjugated linoleic acid (CLA), which may have anti-cancer and other beneficial properties. Yes there are issues affecting over-consumption of milk with the inclusion of growth factor, saturated fat and protein, for the huge percentage of people who are lactase persistent in the UK my thoughts are that the emerging evidence regarding BCM-7 in A1 milk cannot be ignored and that where we, as nutritional therapists, advise clients on elimination, reduction or use of alternative sources of milk for our clients that the alternative of A2 milk is another important consideration. Notably, Professor Boyd Swinburn stated in his Report to the New Zealand Food Safety Authority entitled Beta casein A1 and A2 in milk and human health (2004) that: The appropriate government agencies have several important responsibilities in this matter: to support further research in the area (especially clinical research); to clearly communicate the state of knowledge and judged risks to the public, and; to take specific actions to promote and protect the health of the public, where appropriate. and As a matter of individual choice, people may wish to reduce or remove A1 beta-casein from their diet (or their children s diet) as a precautionary measure. This may be particularly relevant for those individuals who have or are at risk of the diseases mentioned (type 1 diabetes, coronary heart disease, autism and schizophrenia). However, they should do so knowing that there is substantial uncertainty about the benefits of such an approach. In conclusion, while further research is needed to establish a cause-effect relationship between exposure to BCM-7 and the non-communicable conditions, there is evidence to suggest that BCM-7 is linked to various unwanted physiological effects in susceptible individuals. References REFERENCES_BANT_NEWS_JUL2013_ISSUE_50.pdf page 8