a2 Milk™ for gut comfort
Matthew Barnett, AgResearch Limited
April 14th 2016
Host Institution
Overview
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a2 Milk™ – what’s the story?
Where does this project fit in?
What do we hope to achieve?
How are we going to do it?
a2 Milk™ – What’s the Story?
• Bovine milk has >200 different proteins
• One of these is β-casein, which comprises 25-30% of
the total protein
• There are several well-characterised variants in the βcasein gene
• Some of these result in changes to the protein
sequence, with possible functional consequences
a2 Milk™ – What’s the Story?
• Originally, all cows produced only A2
β-casein
• A1 β-casein mutation developed in
some European dairy herds 5-10,000
years ago. This form is now the most
widespread
• Today, most milk contains a mix of A1
and A2 protein types
• a2 milk™ products contain only the
A2 form of β-casein
a2 Milk™ – What’s the Story?
β-casomorphin-7 (BCM-7)
Figure adapted from Gobbetti et al. (2002). Crit Rev Food Sci Nutr 42(3):223-39,
and Jinsmaa & Yoshikawa (1999) Peptides 23(8):957-62
a2 Milk™ – What’s the Story?
β-casomorphin-7 (BCM-7)
Figure adapted from Gobbetti et al. (2002). Crit Rev Food Sci Nutr
42(3):223-39, and Jinsmaa & Yoshikawa (1999) Peptides 23(8):957-62
a2 Milk™ – What’s the Story?
Human β-casein is like A2, not A1, bovine β-casein
• Human, goat and sheep β-casein proteins are comparable to A2
(not A1) protein in terms of structure around BCM-7 release
• Only 1-10% of the theoretical human equivalent comes from in
vitro digestion of human β-casein
• Internal differences mean bovine BCM-7 is 10 x more potent
(opioid receptor binding) than the theoretical human equivalent
T y r 60- P r o 61- P h e 62- P r o 63- G l y 64- P r o 65- l l e 66- H i s 67
Bovine β-casein A1
T y r 60- P r o 61- P h e 62- P r o 63- G l y 64- P r o 65- l l e 66- P r o 67
Bovine β-casein A2
T y r 51- P r o 52- P h e 53- Va l 54- G l u 55- P r o 56- l l e 57- P r o 58
Human β-casein
a2 Milk™ – What’s the Story?
• Interest started with epidemiological studies indicating
differential disease risk associated with A1 and A2 milk
• More recent work in animals and humans has focused on
immediate effects (e.g., digestive comfort)
– Consumers care about the “now”
– Generally accepted that a healthy gut means better overall
health
• Pre-clinical data shows differences resulting from consumption
of standard milk (i.e., containing A1 β-casein) and a2 milk™
(free of A1 β-casein)
– Intestinal transit1
– Inflammatory response1,2
et al. (2014). Int J Food Sci Nutr 65(6):720-7
2Ul Haq et al. (2013). Eur J Nutr 53(4):1039-49
1Barnett
a2 Milk™ – What’s the Story?
• Human clinical data1 showing consumption of
standard vs. a2 milk™ may lead to differences in
– Intestinal comfort
– Intestinal physiology
– Cognitive behaviour
• Mechanisms may relate to the release of different
bioactive peptides
– BCM-7 from A1 β-casein has been shown to trigger
inflammation in human cells in vitro2
– This needs to be consolidated by human studies
et al. (2016). Nutrition Journal 15:35
2Trivedi et al. (2014). J Nutr Biochem 25(10):1011-8
1Jianqin
Where does this project fit in?
• Many consumers in Asia consider themselves to
be “lactose intolerant”
• These consumers avoid consuming dairy products
due to intestinal discomfort
• Recent data suggest this discomfort may be due
to inflammation in the small intestine, which may
in turn be a response to A1 β-casein
Where does this project fit in?
• Evidence of increased intestinal discomfort in
response to A1 milk compared with A2 milk
Jianqin et al. (2016). Nutrition Journal 15:35
Where does this project fit in?
• Evidence of inflammation in response to A1 milk
compared with A2 milk
– Increased serum IL-4, IgG, IgE
How can we build on this evidence?
Jianqin et al. (2016). Nutrition Journal 15:35
What do we hope to achieve?
• Generate evidence that some consumers who
currently avoid dairy can tolerate a2 Milk™
• Better understand the mechanisms through which
this (in)tolerance occurs
• Contribute evidence for a health claim by the a2 Milk
Company
• -> Increased dairy consumption in China
How are we going to do it?
• Test the hypothesis: “that a2 Milk™ does not induce
adverse symptoms of gut discomfort in consumers
with perceived lactose intolerance.”
How are we going to do it?
Clinical studies, standard vs. a2 Milk™
• A range of outcome measures, including
– Self-reported intestinal symptoms/mood/appetite
– Imaging of small intestine
– Plasma
• Metabolites
• Cytokines
– Breath volatile metabolites
How are we going to do it?
• How do these variants influence inflammatory
response?
– Cytokine release from cells
• TNF-α (pro-inflammatory)
• IL-10 (anti-inflammatory)
• IL-4 (pro-inflammatory)
– miRNA release from cells
• miRNAs related to inflammation
Image by kaibara87 - originally posted to Flickr as Cell Culture, CC BY 2.0,
https://commons.wikimedia.org/w/index.php?curid=5618734
In vitro studies, purified and SGID A1 vs. A2 β-casein
Outcomes
• Demonstrate health benefits of a2 Milk™-based
products for improving gut comfort
• Contribute to the a2 Milk Company’s mission:
“to pioneer the scientific understanding of a2 Milk™
so we can bring more people the pleasure and
nutritional goodness that only comes from real and
natural milk.”
Outcomes
• Support the a2 Milk Company to submit a dossier
for a high-level health claim that meets NZ
regulations, and those in key international export
markets.
• Increased value to the NZ supply chain
– Farmers
– Processors
– Ingredient manufacturers
Acknowledgements
• HVN
• The a2 Milk Company Limited
• The University of Auckland
• “a2 Milk™ for Gut Comfort” Team
– Shalome Bassett, David Cameron-Smith, Andrew Clarke, Li Day,
Karl Fraser, Amber Milan, Suzanne Simpson, Wayne Young
Cheers!