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Milk Proteins and Human Health: A1 versus A2 Beta-­‐Casein Monday, 10th August 2015
Professor K aren D wyer -­‐ Nephrologist
Dr J oanna M cM illan
Prof. of M edicine, D eputy H ead o f S chool
School o f M edicine, F aculty o f M edicine a nd H ealth D eakin U niversity
D ietitian | N utrition S cientist
Founder o f D r J oanna® a nd G et L ean
Vice P resident o f t he A ustralian L ifestyle M edicine A ssociation
This webinar is supported proudly by
Learning Objectives
To p rovide a n o verview o n the d ifference b etween A 1 a nd A 2 b eta-­‐casein proteins a nd d iscuss the s cientific e vidence a round b eta-­‐casein p rotein variants a nd p otential impact h uman h ealth • After p articipating in this p rogram, d ietitians w ill b e a ble to:
• Differentiate b etween A 1 a nd A 2 b eta-­‐casein p roteins
• List m ammalian m ilk c ontaining A 1 a nd / o r A 2 b eta-­‐casein g enetic v ariants
• Evaluate t he e vidence for d igestion d ifferences b etween A 1 a nd A 2 b eta-­‐casein protein v ariants
Introduction
• A1 b eta-­‐casein is relevant to d igestive f unction a nd b roader a spects o f h uman health
• This is s omething d ietitians m ight w ish c onsider d uring d ietetic c onsultations
• In 2 014, a n important h uman c ross-­‐over A 1 v ersus A 2 b eta-­‐casein m ilk p rotein study p rovided p reliminary e vidence t hat t hese p rotein v ariants stimulate differences in d igestion responses • we will focus in particular on a recent clinical trial which was published in the European Journal of Clinical Research)
• Over t he last t wo y ears, various a nimal studies h ave reported d ifferences in gastrointestinal o utcomes w ith feeding A 1 v ersus A 2 b eta-­‐casein
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What is Beta-­‐casein?
Beta-­‐casein is a protein present in milk at ~2.5g a glass A1 beta-­casein
A2 beta-­casein
Diagram taken from book entitled ‘The Devil in the Milk’, Woodford, 2007
Beta-­‐casein & B eta-­‐casomorphin Research G oes B ack ~ 40 years
Beta-­‐casein & B eta-­‐casomorphin Research G oes B ack ~ 40 years
BCM -­‐7
BCM -­‐5
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Variants of Beta-­‐casein
• Two key types: A1 or A2 beta-­‐casein types
• A2 is the original form
• A1 is a consequence of a historical mutation to the A2 beta-­‐casein which affects many cattle of European origin
• There are also numerous sub-­‐variants of both A1 and A2. The only one of importance is B which is part of the A1 beta-­‐casein family.
F o rm a g g io n i e t a l. (1 9 9 9 ). M ilk p ro te in p o ly m o rp h is m : D e te c tio n a n d d iffu s io n o f th e g e n e tic v a ria n ts in B o s g e n u s . P a rm a , U n iv e rs iti d e g li S tu d i d e P a rm a , A n n a lli d e lla F a c o lta d i M e d ic in a V e te rin a ria
A1 & A2 Beta-­‐casein in Milk
Holstein c ows’
milk ( m ost c om m on U S, N E urope, Australia & N Z)
Guernsey c ows’
milk
Higher % o f A 2
Goat, water buffalo, sheep, Cattle of Asian origin & human breast milk
50:50 A 1 & A 2
A2 like
A2 c ows’ m ilk a vailable in A ustralia & N Z
The difference between A1 and A2 beta-­‐casein families • The only difference in the 209 amino acid chain of beta-­‐casein is a single amino acid at position 67 (proline in A2 instead of in histidine A1)
• However, this has a profound effect on the way the protein digests. (Kam inski e t a l., 2 007)
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Peptides Released on Digestion
Beta-­‐casom orphin-­‐7 ( BCM -­‐7) o nly r eleased f rom A 1
References
1. Jinsmaa Y, Yoshikawa M. Enzymatic release of neocasomorphin and beta-­‐casomorphin from bovine beta-­‐casein. Peptides. 1999;20(8):957-­‐62
2. Ul Haq et al. Release of beta-­‐casomorphin-­‐7/5 during simulated gastrointestinal digestion of milk beta-­‐casein variants from Indian crossbred cattle (Karan Fries). Food chemistry. 2015;168:70-­‐9
3. Wada Y, Lonnerdal B. Bioactive peptides released from in vitro digestion of human milk with or without pasteurization. Pediatric research. 2015;77(4):546-­‐53
Some Known Effects of Bovine BCM-­‐7
• Under normal digestion conditions in the human gut, BCM-­‐7 is released from A1 beta-­‐casein but not A2 beta-­‐casein (De N oni, 2008; Boutrou et al. 2013)
• Boutrou et al. (2013) published in American Journal of Clinical Nutrition the results of their human feeding study, where they found considerable BCM-­‐7 in jejunal effluents of humans fed milk casein • BCM-­‐7 was present in the jejunal effluent throughout 6 hours of digestion • The amount of BCM-­‐7 detected in the jejunal effluent after 2 hours of digestion was 4 mg BCM-­‐7 released from 30 g of casein • BCM-­‐7 has opioid characteristics and this is the reason for the ‘morphin’ in the name (Henschen, A . 1979)
• BCM-­‐7 has its effects by attaching to mu-­‐opioid receptors (Henschen, A . 1979)
• In humans and other species, gut transit is influenced by mu-­‐opioid receptors. Mu-­‐opioid agonists (like codeine and BCM-­‐7) inhibit peristalsis and slow down the transit of food (Galligan & Akbarali 2014; B arnett et a l. 2 014)
• BCM-­‐7 levels released in the human gut from milk digestion is consistent with pharmacological effects (Boutrou et al. 2013)
Some More Known Effects of Bovine BCM-­‐7
• BCM-­‐7 crosses into circulation of human babies & children ( Kost et a l. 2 009; W asilew ska et a l. 2 011)
• Babies & children -­‐ immature guts and effects of age
• Linked to delayed psychomotor development and Sleep Apnoea events in infants • In vitro ­oxidation of LDL-­‐Chol (Torreilles & G uerin 1 995) • Elevated blood antibodies to oxLDL in formula fed (with casein) vs breast fed babies ( Steinerova et a l. 2 004)
• differences in oxidised LDL b/w formula & breast fed babies mediated via A1 beta-­‐casein derived BCM-­‐7? • BCM-­‐7 is found in the urine of children ( Sokolov et a l. 2 014) • BCM-­‐7 and other casomorphins cross the blood brain barrier (there are mu opioid receptors in the brain) ( Erm isch et a l. 1 983; S un e t a l. 2 003)
•
Links to various mental disorders
• In rats and mice, BCM-­‐7 shown to cause inflammation in the colon ( H aq et a l. 2 014; B arnett e t a l. 2 014)
• In mice, BCM-­‐7 has been shown to cause immune responses in the gut ( H aq et a l. 2 014)
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Recent Studies Investigating A1 vs A2 beta-­‐caseins
A2 b eta-­‐casein s hown t o b e a b etter c haperone t han A 1 b eta-­‐casein. T his m ay b e r elevant t o a v ariety o f s cenarios.
From Prof Carver – personal communications
1)
In a d isease context, p rotein m isfolding and a ggregation o f p roteins m ay b e p revented b etter in A 2-­‐fed m ice w hich w ould lead to reduced s usceptibility to type-­‐2 d iabetes ( since this involves a ggregation o f the p eptide a mylin). •
Amyloid fibril formation is a ssociated w ith t he d eposits found in m any d iseases o f p rotein a ggregation such a s A lzheimer's a nd Parkinson's a nd their formation is intimately linked to these d iseases. In the a bsence o f o ther caseins ( which a ct a s c haperones), kappa-­‐casein is h ighly toxic to cells, w hich correlates w ith its formation o f a myloid fibrils.
2) In a d iary industry p erspective, the g reater c haperone a bility o f A 2 b eta-­‐casein m ight explain w hy it is h arder to m ake h ard c heese from A 2 m ilk ( i.e. the g reater chaperone a bility o f A 2 b eta-­‐casein p revents the p recipitation o f the p ara-­‐kappa-­‐casein following p roteolysis b y rennet). O ur results w ould a lso explain w hy A 1 cows h ave b ecome the p revalent g enetic variant -­‐ they p roduce m ilk that is m ore readily a ble to form c heese a nd h ave b een s elected a ccordingly b y farmers.
R e f: R a y n e s e t a l. S tru c tu ra l d iffe re n c e s b e tw e e n b o v in e A (1 ) a n d A (2 ) b e ta -­‐c a se in a lte r m ic e lle se lf-­‐a sse m b ly a n d in flu e n c e m o le c u la r c h a p e ro n e a c tiv ity . J D a iry S c i. 2 0 1 5 ;9 8 (4 ):2 1 7 2 -­‐8 2
Myeloperoxidase (MPO) in Mice M yeloperoxidase a ctivity in t he ileum . M PO is a m arker o f inflam m ation
M yeloperoxidase i s r eleased f rom s tim ulated p olym orphonuclear neutrophils ( PM N s) t hat p roduce t he pow erful o xidant h ypochlorous acid t hat h as m icrobicidal activity i n a ddition t o t issue d am age s uch a s a cute or c hronic i nflam m ation. T herefore, i t s erves a s a m arker o f i nflam m ation.
R e f: U l H a q e t a l. C o m p a ra tiv e e v a lu a tio n o f c o w b e ta -­‐c a se in v a ria n ts (A 1 /A 2 ) c o n su m p tio n o n T h 2 -­‐m e d ia te d in fla m m a to ry re sp o n se in m o u se g u t. E u r J N u tr. 2 0 1 4 ;5 3 (4 ):1 0 3 9 -­‐4 9 Myeloperoxidase (MPO) in Rats M yeloperoxidase a ctivity in t he j ejunum . M PO is a m arker o f inflam m ation
Data a re m eans ± standard e rror o f the m ean. M PO: m yeloperoxidase; A 1S: A 1 b eta-­‐casein p lus saline; A 1N: A 1 b eta-­‐casein p lus n aloxone; A2S: A 2 b eta-­‐casein p lus saline; A 2N: A 2 b eta-­‐casein p lus n aloxone. * p<0.05 versus a ll o ther g roups.
R e f: B a rn e tt e t a l. D ie ta ry A 1 b e ta -­‐c a se in a ffe c ts g a stro in te stin a l tra n sit tim e , d ip e p tid y l p e p tid a se -­‐4 a c tiv ity , a n d in fla m m a to ry sta tu s re la tiv e to A 2 b e ta -­‐c a se in in W ista r ra ts. In t J F o o d S c i N u tr. 2 0 1 4 ;6 5 (6 ):7 2 0 -­‐7 . 5
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DPP-­‐4 Enzyme In Rats
DPP-­‐4 a ctivity in t he j ejunum . D PP-­‐4 e nzym e c leaves B CM -­‐7, r esulting in t he loss o f o pioid a ctivity. H ere A 1 feeding increases D PP-­‐4 level, w ith & w ithout n aloxone, m eaning t he increase d oes n ot d epend o n t he o pioid a ctivity o f A 1
Data a re m eans ± standard e rror o f the m ean. D PP-­‐4: d ipeptidyl p eptidase 4 ; A 1S: A 1 b eta-­‐casein p lus saline; A 1N: A 1 b eta-­‐casein plus n aloxone; A 2S: A 2 b eta-­‐casein p lus saline; A 2N: A 2 b eta-­‐casein p lus n aloxone. * *p<0.01 versus A 2S.
R e f: B a rn e tt e t a l. D ie ta ry A 1 b e ta -­‐c a se in a ffe c ts g a stro in te stin a l tra n sit tim e , d ip e p tid y l p e p tid a se -­‐4 a c tiv ity , a n d in fla m m a to ry sta tu s re la tiv e to A 2 b e ta -­‐c a se in in W ista r ra ts. In t J F o o d S c i N u tr. 2 0 1 4 ;6 5 (6 ):7 2 0 -­‐7 . Total IgE antibodies in Mice Total IgE antibodies in t he ileum Different letters indicate (p<0.05)
IgE production m anifests as various allergic diseases including food allergy. T he significance of this Total IgE
production in the gut is ??????
R e f: U l H a q e t a l. C o m p a ra tiv e e v a lu a tio n o f c o w b e ta -­‐c a se in v a ria n ts (A 1 /A 2 ) c o n su m p tio n o n T h 2 -­‐m e d ia te d in fla m m a to ry re sp o n se in m o u se g u t. E u r J N u tr. 2 0 1 4 ;5 3 (4 ):1 0 3 9 -­‐4 9 Interleukin 4 (IL-­‐4) in Mice Interleukin 4 in t he ileum D ifferent l etters indicate ( p<0.05)
CD4 T-cells secrete IL-4 that differentiates Th0-Th2 cells and induces class-switching recombination to IgG & IgE isotopes.
Here, see an
increase (p<0.01) in IL-4 levels with A1A1 & A1A2 beta-casein variants consumption by 266 & 277% versus control mice.
These results also indicated an increase (p<0.01) in IL-4 levels on feeding A1A1 and A1A2 beta-casein by 272 & 282%, respectively, compared to
A2A2 consumption. No changes were observed on feeding A2A2 beta-casein compared to control group mice.
R e f: U l H a q e t a l. C o m p a ra tiv e e v a lu a tio n o f c o w b e ta -­‐c a se in v a ria n ts (A 1 /A 2 ) c o n su m p tio n o n T h 2 -­‐m e d ia te d in fla m m a to ry re sp o n se in m o u se g u t. E u r J N u tr. 2 0 1 4 ;5 3 (4 ):1 0 3 9 -­‐4 9 6
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NOD mice - A1 decreased lactase enzymes vs A2
Lactase Gene Expression in gut tissues from NOD m ice
on A1 or A2 beta-casein diet for 10 & 20 weeks
L o w e r leve ls o f
la c ta se ge n e in th e
A 1 fe d m ic e
A 2 b e ta -c a se in fe d la c ta se leve ls
A 1 b e ta -c a se in fe d la c ta se leve ls
D w y e r e t a l., (2 0 1 5 ) u n p u b lis h e d d a ta
BCM-­‐7 Sensitivity Varies Between People M u o pioid g ene e xpression in c ontrols v ersus t hose w ith A topic D erm atitis ***p < 0.001
control (1μg/ml BCM-­‐7) vs AD group (1μg/ml BCM-­‐7) ***p < 0.001
control (1ng/ml BCM-­‐7) vs AD group (1ng/ml BCM-­‐7) Atopic D ermatitis Com parison o f t he M O R g ene e xpression c hanges i n P eripheral B lood M ononuclear C ells i n C ontrol a nd A topic D erm atitis groups u nder t he i nfluence o f B CM -­‐7 i n t he c oncentration o f 1 μg /m l a nd 1 ng /m l
Ref: Fiedorowicz et al. beta-­‐casomorphin-­‐7 alters mu-­‐opioid receptor and dipeptidyl peptidase IV genes expression in children with atopic dermatitis. Peptides. 2014;62:144-­‐9. BCM-­‐7 Sensitivity Varies Between People DPP-­‐4 g ene e xpression in c ontrols v ersus t hose w ith A topic D erm atitis *p < 0.05 control (1μg/ml BCM-­‐7) vs AD group (1 g /ml BCM-­‐7) ***p < 0.001
control (1ng/ml BCM-­‐7) vs AD group (1ng/ml BCM7) Atopic Dermatitis Com parison o f t he D PP-­‐4 g ene e xpression c hanges in P eripheral B lood M ononuclear C ells i n C ontrol a nd A topic D erm atitis g roups u nder t he i nfluence o f B CM -­‐7 i n t he c oncentration o f 1 μg /m l a nd 1 ng /m l
Ref: Fiedorowicz et al. beta-­‐casomorphin-­‐7 alters mu-­‐opioid receptor and dipeptidyl peptidase IV genes expression in children with atopic dermatitis. Peptides. 2014;62:144-­‐9. 7
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Heart Disease and A1 Beta-­‐casein
r 2 =0.86; p<0.00001
R e f: M c L a c h la n C N S , M e d ica l H y p o th e se s 2 0 0 1
Snapshot up to Here…….
• The s cience is c lear t hat u nder n orm al d igestion A 1 b eta-­‐casein releases B CM -­‐7 whereas A 2 d oes n ot
• The s cience is c lear t hat B CM -­‐7 is a m u-­‐opioid receptor a gonist
• The s cience is c lear t hat B CM -­‐7 h as p hysiological e ffects w hen fed to v arious a nimal species ( including a dditional t rials n ot d iscussed h ere)
• The s cience is c lear t hat t here a re in v itro e ffects o n h uman c ells • At t he p opulation level, t he e pidemiology s trongly links t he intake o f A 1 b eta-­‐casein to Type 1 D iabetes a nd H eart D isease t o ( note: a lthough t he a ssociations are proven, e pidemiology d oes n ot p rove c ausation)
• So t here a re lots o f s trong indications
• Random ised, b linded h um an c linical t rials h ave b een n eeded ( these a re e xpensive and f unding for s uch t rials is v ery d ifficult t o a cquire) Human Clinical Trial (Curtin University)
• 41 p articipants, all o f w hom spent two w eeks o n each o f an A 1 b eta-­‐casein and an A 2 b eta-­‐casein m ilk d iet, w ith the o rder randomly assigned, w ith a two w eek w ashout p eriod b oth b efore and b etween the treatments • 31 o f the p articipants w ere n ormal m ilk d rinkers and considered themselves to h ave n o intolerance to m ilk.
•
10 d id consider themselves to h ave an intolerance issue b ut m ost o f these still n ormally consumed m ilk products.
• Five w ithdrew d uring the trial (four o n the A 1 arm)
Ref: Ho et al. Comparative effects of A1 versus A2 beta-­‐casein on gastrointestinal measures: a blinded randomised cross-­‐over pilot study. Eur J Clin Nutr. 2014;68 (9):994-­‐1000
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Comparative Effects of A1 versus A2 Beta-­‐casein on Gastrointestinal Measures: A Blinded Randomised Cross-­‐over Pilot Study
• Interpretation/explanation: The softer stools o n the A 1 b eta-­‐casein containing d iet likely the result o f delayed G ITT a ffording increased o pportunity for fermentable contents in the g ut, including lactose, to undergo fermentation Ref: Ho et al. Comparative effects of A1 versus A2 beta-­‐casein on gastrointestinal measures: a blinded randomised cross-­‐over pilot study. Eur J Clin Nutr. 2014;68 (9):994-­‐1000
Human Cross-­‐over A1 versus A2 beta-­‐casein Milk Study -­‐
Pain and Looser stools on A1 but NOT on A2
• There was a significant positive association between abdominal pain and stool consistency on the A1 diet (r =0.520, p=0.001), but not the A2 diet (r =-­‐0.13, p=0.43). The difference between these two correlations (0.52 versus -­‐0.13) was highly significant (p<0.001)
• Interpretation/explanation: Slower GITT caused by A1 beta-­‐casein containing milk increased opportunities for fermentable gut contents to undergo fermentation, which did not occur with the A2 beta-­‐casein containing milk diet
Ref: Ho et al. Comparative effects of A1 versus A2 beta-­‐casein on gastrointestinal measures: a blinded randomised cross-­‐over pilot study. Eur J Clin Nutr. 2014;68 (9):994-­‐1000
Human Cross-­‐over A1 versus A2 beta-­‐casein Milk Study -­‐
Faecal Calprotectin Results
• There w ere n o s ignificant o verall d ifferences b etween t reatments • However, t here w ere 5 c ases w here values w ere a bove 5 0 m icrograms/ml a nd a ll o f these h ad t he A 1 d iet f irst
• There w ere t hree c ases t hat h ad a bnormally h igh F C values o n t he A 1 a rm b ut n ot t he A 2
• FC c orrelated m uch m ore strongly w ith intolerance m easures w hile o n t he A 1 a rm o f t he trial t han o n t he A 2 a rm Elevated faecal c alprotectin i ndicates t he m igration o f n eutrophils t o t he i ntestinal m ucosa, w hich o ccurs d uring i ntestinal i nflam m ation, including i nflam m ation c aused b y i nflam m atory b ow el d isease
Ref: Ho et al. Comparative effects of A1 versus A2 beta-­‐casein on gastrointestinal measures: a blinded randomised cross-­‐over pilot study. Eur J Clin Nutr. 2014;68 (9):994-­‐1000
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Human Cross-­‐over A1 versus A2 beta-­‐casein Milk Study -­‐
Faecal Calprotectin Results
The difference in the correlation measures between the A1 and A2 diets was significant for:
• abdominal pain (0.46 vs 0.03; P=0.02); and • bloating (0.36 vs − 0.02; P=0.05) Ref: Ho et al. Comparative effects of A1 versus A2 beta-­‐casein on gastrointestinal measures: a blinded randomised cross-­‐over pilot study. Eur J Clin Nutr. 2014;68 (9):994-­‐1000
Gastrointestinal Symptoms Among Those W hom Considered Themselves M ilk Intolerant Before Study Entry (n=8) Im portant t o c onsider c linical v ersus s tatistical s ignificance Ref: Ho et al. Comparative effects of A1 versus A2 beta-­‐casein on gastrointestinal measures: a blinded randomised cross-­‐over pilot study. Eur J Clin Nutr. 2014;68 (9):994-­‐1000
Interpretation of the A1 vs A2 beta-­‐casein in M ilk Human Study Results
In relation to faecal consistency and intolerance symptoms a) there are real and statistically conclusive d ifferences b etween the treatments: A 1 a nd A 2 b eta-­‐casein d o have d ifferent e ffects o n d igestive function
• Small study n umbers is n ot a flaw h ere, g iven the r esults a re s ignificant & stem from a r andomly r ecruited r epresentative p opulation
b) the results are consistent w ith p rior knowledge about B CM-­‐7 release and the known associated science about B CM-­‐7 b eing a m u-­‐opioid receptor agonist
c) the effects are consistent w ith d elayed gut transit resulting in increasing food fermentation, and also thereby exacerbating any lactose m alabsorption
d) the looser stools o n A 1 (rather than firmer stools/constipation) are consistent w ith empirical d ata from animal trials in relation to inflammation w hich w ill affect w ater absorption in the colon e) although some p eople w ill b e affected m ore than o thers, there is evidence for subclinical d ifferences even among those w ith n o identified m ilk intolerance
f) M ilk types free o f A 1 b eta-­‐casein are a real o ption to b ring p eople b ack to m ilk w ho o therwise avoid it because o f intolerance issues Ref: Ho et al. Comparative effects of A1 versus A2 beta-­‐casein on gastrointestinal measures: a blinded randomised cross-­‐over pilot study. Eur J Clin Nutr. 2014;68 (9):994-­‐1000
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FSANZ: Review of A1 /A2 Milk • 2004 Food Safety Authority New Zealand (FSANZ) review on A1/A2 Milk food safety • Undertaken b y P rofessor B oyd Swinburn, P rofessor o f Professor o f Population N utrition a nd G lobal H ealth
(New Zealand)
• A quote from Professor Swinburn’s report
“if I h ad a c hild w ith T ype 1 d iabetes a nd w as d ue t o h ave a nother a nd I c ould easily o btain a nd a fford A 2 m ilk o r f orm ula, I w ould c ertainly u se it f or t he n ext child b ecause t he c ost/benefit is low b ecause o f t he p otentially v ery large b enefit of p reventing T ype 1 d iabetes”
Swinburn B. Beta-­‐casein A1 and A2 in milk and human health Report to New Zealand Food Safety Authority. Prepared for New Zealand Food Safety Authority July 2004
European Food S afety Report (EFSA)-­‐ 2009
• EFSA reviewed existing data and information on the effects of BCMs & related peptides on human health in 2009, specifically in the cause of non-­‐communicable diseases (heart disease and type 1 diabetes) • Beta-­‐casein & beta-­‐casomorphin research has progressed considerable since then
• Concluded that there existed no conclusive proof of ‘cause & effect’ regarding exposure to BCM-­‐7 & disease risk • More specifically, that more data was needed on its production, absorption into the body and crossing into the brain (we now have such data, and we now know that bovine BCM-­‐7 is absorbed into circulation of infants)
• It also identified that some sectors of the population, such as babies and adults with certain diseases, may be more likely to be affected by BCM-­‐7 • Identified that BCM-­‐7 can affect various organs and tissues including digestive, immune and neurological (but made an obvious error in the summary where it says "A prerequisite for opioid activity after oral ingestion is that the peptides must pass the intestinal epithelial barrier". Scientific Report of EFSA prepared by a DATEX Working Group on the potential health impact of beta-­‐casomorphins and related peptides. EFSA Scientific Report (2009). 231, 1-­‐107 EFSA Report, 2009;; Available at URL: http://edepot.wur.nl/8139
Overall Conclusion
There is now conclusive evidence that A1 beta-­‐casein is indeed relevant to broad-­‐based issues of human health
This webinar is supported proudly by
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Cited References
1.
B a rn e tt M P , M c N a b b W C , R o y N C , W o o d fo rd K B , C la rk e A J. D ie ta ry A 1 b e ta -­‐c a se in a ffe c ts g a stro in te stin a l tra n sit tim e , d ip e p tid y l p e p tid a se -­‐4 a c tiv ity , a n d in fla m m a to ry sta tu s re la tiv e to A 2 b e ta -­‐c a se in in W ista r
ra ts. In t J F o o d S c i N u tr. 2 0 1 4 ;6 5 (6 ):7 2 0 -­‐7 . 2.
B o u tro u R , G a u d ic h o n C , D u p o n t D , Ja rd in J, A irin e i G , M a rsse t-­‐B a g lie ri A , e t a l. S e q u e n tia l re le a se o f m ilk p ro te in -­‐d e riv e d b io a c tiv e p e p tid e s in th e je ju n u m in h e a lth y h u m a n s. A m J C lin N u tr. 2 0 1 3 ;9 7 (6 ):1 3 1 4 -­‐
3.
B ra n tl V , T e sc h e m a c h e r H . A m a te ria l w ith o p io id a c tiv ity in b o v in e m ilk a n d m ilk p ro d u c ts. N a u n y n S c h m ie d e b e rg s A rc h P h a rm a c o l. 1 9 7 9 ;3 0 6 (3 ):3 0 1 -­‐4 .
4.
5.
D e N o n i I. R e le a se o f b -­‐c a so m o rp h in s 5 a n d 7 d u rin g sim u la te d g a stro -­‐in te stin a l d ig e stio n o f b o v in e b -­‐c a se in v a ria n ts a n d m ilk -­‐b a se d in fa n t fo rm u la s. F o o d c h e m istry . 2 0 0 8 1 1 0 (4 ):8 9 7 -­‐9 0 3 .
E rm isc h A , R u h le H .J, N e u b e rt K , H a rtro d t B , L a n d g ra f R , (1 9 8 3 ). O n th e b lo o d -­‐b ra in b a rrie r to p e p tid e s: [3 H ]b e ta -­‐c a so m o rp h in -­‐5 u p ta k e b y e ig h te e n b ra in re g io n s in v iv o . J N e u ro c h e m . 4 1 (5 ), 1 2 2 9 -­‐3 3 . 6.
F ie d o ro w ic z E , K a c z m a rsk i M , C ie slin sk a A , S ie n k ie w ic z -­‐S z la p k a E , Ja rm o lo w sk a B , C h w a la B , e t a l. b e ta -­‐c a so m o rp h in -­‐7 a lte rs m u -­‐o p io id re c e p to r a n d d ip e p tid y l p e p tid a se IV g e n e s e x p re ssio n in c h ild re n w ith 7.
a to p ic d e rm a titis. P e p tid e s. 2 0 1 4 ;6 2 :1 4 4 -­‐9 . F o rm a g g io n i e t a l. (1 9 9 9 ). M ilk p ro te in p o ly m o rp h ism : D e te c tio n a n d d iffu sio n o f th e g e n e tic v a ria n ts in B o s g e n u s. P a rm a , U n iv e rsiti d e g li S tu d i d e P a rm a , A n n a lli d e lla F a c o lta d i M e d ic in a V e te rin a ria
8.
G a llig a n JJ, A k b a ra li H I. M o le c u la r P h y sio lo g y o f E n te ric O p io id R e c e p to rs. A m J G a stro e n te ro l. 2 0 1 4 ;2 (1 ):1 7 -­‐2 1 .
9.
H e n sc h e n A , L o ttsp e ic h F , B ra n tl V , T e sc h e m a c h e r H . N o v e l o p io id p e p tid e s d e riv e d fro m c a se in (b e ta -­‐c a so m o rp h in s). II. S tru c tu re o f a c tiv e c o m p o n e n ts fro m b o v in e c a se in p e p to n e . H o p p e S e y le rs Z P h y sio l
2 3 . C h e m . 1 9 7 9 ;3 6 0 (9 ):1 2 1 7 -­‐2 4 .
10.
H o S , W o o d fo rd K , K u k u lja n S , P a l S . C o m p a ra tiv e e ffe c ts o f A 1 v e rsu s A 2 b e ta -­‐c a se in o n g a stro in te stin a l m e a su re s: a b lin d e d ra n d o m ise d c ro ss-­‐o v e r p ilo t stu d y . E u r J C lin N u tr. 2 0 1 4 ;6 8 (9 ):9 9 4 -­‐1 0 0 0 .
11.
Jin sm a a Y , Y o sh ik a w a M . E n z y m a tic re le a se o f n e o c a so m o rp h in a n d b e ta -­‐c a so m o rp h in fro m b o v in e b e ta -­‐c a se in . P e p tid e s. 1 9 9 9 ;2 0 (8 ):9 5 7 -­‐6 2
12.
K o st N .V , S o k o lo v O .Y , K u ra so v a O .B , D m itrie v A .D , T a ra k a n o v a J.N , G a b a e v a M .V , e t a l. (2 0 0 9 ). B e ta -­‐c a so m o rp h in s-­‐7 in in fa n ts o n d iffe re n t ty p e o f fe e d in g a n d d iffe re n t le v e ls o f p sy c h o m o to r d e v e lo p m e n t. P e p tid e s. 3 0 (1 0 ), 1 8 5 4 -­‐6 0
13.
L a u g e se n a n d E llio tt N Z M J 2 0 0 3 14.
M c L a c h la n C N . b e ta -­‐c a se in A 1 , isc h a e m ic h e a rt d ise a se m o rta lity , a n d o th e r illn e sse s. M e d H y p o th e se s. 2 0 0 1 ;5 6 (2 ):2 6 2 -­‐7 2 .
15.
R a y n e s JK , D a y L , A u g u stin M A , C a rv e r JA . S tru c tu ra l d iffe re n c e s b e tw e e n b o v in e A (1 ) a n d A (2 ) b e ta -­‐c a se in a lte r m ic e lle se lf-­‐a sse m b ly a n d in flu e n c e m o le c u la r c h a p e ro n e a c tiv ity . J D a iry S c i. 2 0 1 5 ;9 8 (4 ):2 1 7 2 -­‐8 2
16.
17.
S o k o lo v O , K o st N , A n d re e v a O , K o rn e e v a E , M e sh a v k in V , T a ra k a n o v a Y , e t a l. A u tistic c h ild re n d isp la y e le v a te d u rin e le v e ls o f b o v in e c a so m o rp h in -­‐7 im m u n o re a c tiv ity . P e p tid e s. 2 0 1 4 ;5 6 C :6 8 -­‐7 1 S u n Z , C a d e R . F in d in g s in n o rm a l ra ts fo llo w in g a d m in istra tio n o f g lia d o rp h in -­‐7 (G D -­‐7 ). P e p tid e s. 2 0 0 3 ;2 4 (2 ):3 2 1 -­‐3 . 18.
S c ie n tific R e p o rt o f E F S A p re p a re d b y a D A T E X W o rk in g G ro u p o n th e p o te n tia l h e a lth im p a c t o f b e ta -­‐c a so m o rp h in s a n d re la te d p e p tid e s. E F S A S c ie n tific R e p o rt (2 0 0 9 ). 2 3 1 , 1 -­‐1 0 7 19.
S te in e ro v a A , K o ro tv ic k a M , R a c e k J, R a jd l D , T re fil L , S to z ic k y F , e t a l (2 0 0 4 ). S ig n ific a n t in c re a se in a n tib o d ie s a g a in st o x id iz e d L D L p a rtic le s (Ig o x L D L ) in th re e -­‐m o n th o ld in fa n ts w h o re c e iv e d m ilk fo rm u la . A th e ro sc le ro sis. 1 7 3 (1 ), 1 4 7 -­‐8 . 20.
S w in b u rn B . B e ta -­‐c a se in A 1 a n d A 2 in m ilk a n d h u m a n h e a lth R e p o rt to N e w Z e a la n d F o o d S a fe ty A u th o rity . P re p a re d fo r N e w Z e a la n d F o o d S a fe ty A u th o rity Ju ly 2 0 0 4
21.
T o rre ille s J, G u e rin M C . C a se in -­‐d e riv e d p e p tid e s c a n p ro m o te h u m a n L D L o x id a tio n b y a p e ro x id a se -­‐d e p e n d e n t a n d m e ta l-­‐in d e p e n d e n t p ro c e ss. C R S e a n c e s S o c B io l F il. 1 9 9 5 ;1 8 9 (5 ):9 3 3 -­‐4 2
22.
U l H a q M R , K a p ila R , S h a rm a R , S a lig a n ti V , K a p ila S . C o m p a ra tiv e e v a lu a tio n o f c o w b e ta -­‐c a se in v a ria n ts (A 1 /A 2 ) c o n su m p tio n o n T h 2 -­‐m e d ia te d in fla m m a to ry re sp o n se in m o u se g u t. E u r J N u tr. 2 0 1 4 ;5 3 (4 ):1 0 3 9 -­‐
4 9 . 23.
U l H a q e t a l. R e le a se o f b e ta -­‐c a so m o rp h in -­‐7 /5 d u rin g sim u la te d g a stro in te stin a l d ig e stio n o f m ilk b e ta -­‐c a se in v a ria n ts fro m In d ia n c ro ssb re d c a ttle (K a ra n F rie s). F o o d c h e m istry . 2 0 1 5 ;1 6 8 :7 0 -­‐9
24.
W a d a Y , L o n n e rd a l B . B io a c tiv e p e p tid e s re le a se d fro m in v itro d ig e stio n o f h u m a n m ilk w ith o r w ith o u t p a ste u riz a tio n . P e d ia tric re se a rc h . 2 0 1 5 ;7 7 (4 ):5 4 6 -­‐5 3
25.
W a sile w sk a J, S ie n k ie w ic z -­‐S z la p k a E , K u z b id a E , Ja rm o lo w sk a B , K a c z m a rsk i M , K o sty ra E . T h e e x o g e n o u s o p io id p e p tid e s a n d D P P IV se ru m a c tiv ity in in fa n ts w ith a p n o e a e x p re sse d a s a p p a re n t life th re a te n in g e v e n ts (A L T E ). N e u ro p e p tid e s. 2 0 1 1 ;4 5 (3 ):1 8 9 -­‐9 5
For Further Information
• For a written review of recent literature, go to: https://drjoanna.com.au/blog/a1-­‐vs-­‐a2-­‐milk-­‐blog-­‐383/
• For a pdf of the EJCN Clinical study paper, go to:
https://keithwoodford.files.wordpress.com/2014/08/ho-­‐et-­‐al-­‐ejcn.pdf
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