A1 beta-casein, gut inflammation and immune reactions

A recent paper published in the European Journal of Nutrition provides particularly strong evidence that A1 beta-casein causes gut inflammation and associated immune effects relative to A2 beta-casein. The trials were conducted with mice and, using normal scientific criteria, the results are sufficiently strong that the differences under these research conditions can be described as ‘conclusive’.

This research has the potential to give a great boost to the campaign against A1 beta-casein. Milks that are free of A1 beta casein include all goat milk, all sheep milk, all pure Asian cattle, and all ‘A2 milk’ from cattle. Human milk is also free of A1 beta-casein. It is only the milk from a large proportion of European-origin cattle that produce the mutant A1 beta-casein.

The work was conducted at the Animal Biochemistry Division at the National Dairy Research Institute in India. The lead author is Dr Mohammad Raies Ul Haq.

The trial had four groups of mice. The control group were fed a standard diet of mice chow. The other groups were fed the same chow but in addition were dosed each day with 85 mg (less than one tenth of a gram) of beta-casein of either the A1 type (written as A1A1), or the A2 type (written as A2A2) or an A1A2 mix.  The control group were dosed with a saline fluid to maintain comparability of handling.

In all, the trial produced statistically significant difference for eleven different measures of digestive function. These include a range of inflammation markers, various types of antibodies, and immunity regulators. 

In the interests of brevity, in this post I will present the figures for just two of the measures, these being intestinal myeloperoxidase (MPO) and interleukin-4 (IL-4). Other physiological measures for which statistically significant differences were found, but which I don’t present here, include monocyte chemotactic protein-1, IgE, IgG, IgG1, IgG2a, IgA, TLR-4, and TLR-2.

Myeloperoxidase (MPO)
MPO is an enzyme contained within neutrophils, which are a type of white blood cell. MPO is widely regarded as a classic marker of inflammation. Elevated levels of MPO are also associated with increased risk of heart disease and there is an extensive medical literature on this.

In the figure below taken from the Ul Haq paper, it is evident that whereas there is no difference between the control and A2A2 treatment, the MPO levels are considerably higher for both the A1A2 and the A1A1 treatments.   The common letter ‘a’ for the control and A2A2 treatments indicates that any apparent differences between the control and the A2A2 treatment are statistically non-significant. However, because the other treatments have different letters above them, this indicates that the MPO levels for the A1A2 and A1A1 treatments are statistically significantly different both to the other treatments and to each other.  The small lines above each  treatment are called ‘error bars’ and provide to those trained in statistics a visual indication of the confidence that can be held in the apparent differences being real and repeatable. Within the text of the paper, it is reported that “feeding of A1A1 and A1A2 beta-casein variants increased MPO activity in murine [mouse] intestine (p<0.01) by 204.20 and 43.54% respectively, compared to control group mice”

Intestinal myeloperoxidase

Intestinal myeloperoxidase

Interleukin-4 (Il-4) leads to development of  a particular type of T cells called Th2 cells. An increase in Th2 production is an immune response; i.e. the body is reacting against a foreign substance.   Overproduction of IL-4 is also associated with some allergies, including eczema, asthma and urticaria (hives).

In the graph below it is evident that there is no difference between interleukin-4 production between the control and A2A2 treatments. (They both have a common letter ‘a’.) However the values for the A1A1 and A1A2 treatments are both much higher.  The text states that “the current study revealed an increase (p<0.01) in IL-4 levels in murine intestinal fluid on consumption of A1A1 and A1A2 beta-casein variants by 266.12 and 277.41% compared to control group mice”.    (Remember that dealing in percentages can sometimes be a little confusing. An increase of 266% means that the levels had been increased by a factor of 3.66 times.)



So what does this mean?
For quite some time the science has been very clear that  A1 beta-casein digests differently than A2 beta-casein ,  i.e. that beta-casomorphin-7 (BCM-7) is released from the A1 but not the A2 beta-casein. However, it has not previously been proven in a trial situation that this leads to physiological responses by the immune system.   What Ul Haq and colleagues have shown is that not only do such differences occur but they are profound.  In summary, the results of this study show unequivocally that ‘there is a difference’.

These proven differences in relation to physiological functioning do not in themselves prove that the A1 beta casein causes any particular disease. However, where there is smoke there is almost certainly going to be fire.  The results fit perfectly with prior claims relating to digestive function, a range of auto immune conditions, and heart disease.

Is there a counter argument?
It is inevitable that the mainstream dairy industry will try to downplay these results. What else can they do in the battle for survival? However, the challenge for those who wish to argue against this paper is that:
a) The research protocol is very strong
b) The results are very strong from a statistical perspective.
c) The paper has been through peer review and is published in a highly rated  international journal.

Nevertheless, my expectation is that the paper will be attacked on multiple grounds, to all of which there is a counter.

  1. The attack: This work was undertaken in mice. How do we know the same effects will occur in humans?
    The answer: For obvious reasons, many trials can only be done with animals. Mice are an accepted model for investigating intestinal conditions. The structure of the intestines of mice and humans is fundamentally very similar, as are the enzymes and immune systems.
  2. The attack: This research needs to be repeated in a Western country before we can place credence on the results.
    The answer: Undertaking similar trials in other countries would and will reinforce the very strong messages of this trial. Indeed I am aware of a trial in a Western country, which has been completed but not yet published, that will confirm key results of the Ul Haq study.
  3.  The attack: The amounts of beta-casein used in this trial were high. Many substances if fed in high enough doses will have nasty effects.
    The answer: The dose rate of beta-casein appears to be broadly similar to what a mouse might eat on an all milk diet, given that mice are voracious eaters. But the key issue is that the effect only occurs with the A1 beta-casein and not the A2 beta-casein.  Even if the differences are much less for humans on human diets, this would still be very worrying in terms of the long-term effects.

So in summary, the Ul Haq et al paper is a significant step forward in relation to the ongoing scientific debate about A1 versus A2 beta-casein.  I know which side of the debate I want to be on.

Ul Haq MR, Kapila R, Sharma R, Saliganta V, Kapila S. 2013 “Comparative evaluation of cow β-casein variants (A1/A2) consumption on Th2-mediated inflammatory response in mouse gut”. European Journal of Nutrition. DOI 10.1007/s00394-013-0606-7 [Epub ahead of print].

The Abstract of this paper is shown below (click once on the Abstract for larger view).

ul haq abstract

Disclosure: Keith Woodford consults as an independent adviser to A2 Corporation.

About Keith Woodford

Keith Woodford is an independent consultant, based in New Zealand, who works internationally on agri-food systems and rural development projects. He holds honorary positions as Professor of Agri-Food Systems at Lincoln University, New Zealand, and as Senior Research Fellow at the Contemporary China Research Centre at Victoria University, Wellington.
This entry was posted in A1 and A2 milk, Agribusiness, Dairy. Bookmark the permalink.

17 Responses to A1 beta-casein, gut inflammation and immune reactions

  1. Luke says:

    A lot of great information about casein and it’s affects on the body.

  2. ksxmeng says:

    Finally had a better understanding about this paper!

  3. Max Dench says:

    Very good research work being done on A2
    I have a question though regarding meat (beef).
    As A2 is a protein, would it also have a similar affect in beef and as a consequence should we ensure we are producing beef from A2 cows in the same way as producing milk from A2 cows?
    I have been breeding a dual purpose breed of cattle for many years purely as a beef herd but recently started A2 testing all the herd with the aim of getting the whole herd to A2A2 and then commencing milking. We are nearly there. I have been asked the above question on a number of occasions from people interested in what we are doing.

    • Keith Woodford says:

      Currently I have no evidence that the A1/A2 issue is relevant to beef.
      In beef herds, cows with the A1 allele will be providing A1 beta-casein to their calves in their milk. But I do not recall evidence as to any effects on the calf. I think there may be one paper that found BCM7 in the calf intestine but I will have to search (when I get a spare moment) for that paper. What effect it might have on the calf has, to the best of my knowledge, not been researched. If there is an opioid effect it might make the calf more placid, but that is only suppopsition.

      • Max Dench says:

        Thanks Keith but I wasn’t meaning via a calf drinking either A1 or A2 milk. I was referring to the protein in the beef of an A2 animal. Is this protein different in a similar way to the difference in the protein in the milk of A2 cows as compared to A1 cows.
        The A1 or A2 gene shows up in DNA tests be it on cows, bulls, steers or calves so is it possible it could mean a difference also in the beef and not only in the milk. That is the question I am being asked.
        You may have answered this in your first sentence in your reply, but does that mean there is no evidence or there has been no studies done, same as there were at one point no studies done on the milk issue and therefore no evidence there either.

      • Angie Pooke says:

        I have various intolerances and for years, thought beef was a problem. Have just discovered that I am fine with A2 milk so like Max, I can’t help thinking that there may be something in the beef as well. I would really like to try A2 beef and would hope that the scientific community will look into this. It seems logical that cows that produce A1 milk would also have that protein in the meat but I have no scientific knowledge. It would be good to finally get some answers.

        A2 milk REALLY needs to be better marketed. (I now need to find out if A2 cream is readily available). I only found out about it by chance and it could be life changing for so many people. If it follows that A2 beef is also better for those of us with IBS, then that would be absolutely dramatic.

      • Keith Woodford says:

        Angie, I know of no-one who is working on this. I have always taken the position that the mutation that leads to production of A1 beta-casein is specific to milk. I think that position is consistent with the known science. But I will do some mre thinking on this.
        Keith W

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  5. Sharon Haylock says:

    Hi Keith,
    A very interesting piece of research.
    I am a Registered Nurse in regional Queensland who heard you speak at the Women’s & Childrens Health Update in Brisbane on 21st June, 2014. Firstly, may I commend you on an excellent presentation that really opened my eyes & made me wonder if I had been living my life under a rock for the past few years! ( Just snowed under with work & Motherhood I think!). I had seen A2 milk on the supermarket shelf, but thought it was probably just another gimmick & never looked into what it was. Perhaps, I took particular interest as my 18 year old daughter recently developed a new onset of one of the worst cases of eczema that I have seen in many years. The A2 Platinum stand sent me a copy of your book “Devil in the Milk” & (I know that while you said yourself on the day it is due for an update again) ; it made for absolutely compelling reading for any health professional. I felt that it was very well researched,& very well written. My husband & I are both from farming backgrounds, in fact his grandfather had a Guernsey stud on this property originally. His comments were that any dairy farmer who is not at least passively switching their herd to A2 would have to be an “Ostrich” ( we say here, burying ones head in the sand). Thank you, for bringing all the research together in this one easy to read book and for your tenacious and independent pursuit of the truth on this subject; despite the attempts of many others to silence or downplay its importance. I hope & pray that science and the truth wins out in the end. Unfortunately, I have recently found another company in Australia with some very dodgy labelling of their milk, pertaining to A2 milk. I didn’t have my reading glasses with me & assumed they had started selling A2 milk – how wrong I was! I will be referring it to the ACCC.

  6. emmaline says:

    Will eating meat from an A2 cow have a similar effect as drinking milk from an A2 cow?

  7. emmaline says:

    Or rather will eating meat from an A1 cow have the same bad health effects as drinking milk from an A1 cow.. Ie is the protein found in meat?

    • Keith Woodford says:

      Currently there is no evidence that there is any problem with the meat from animals that produce A1 beta-casein. And I doubt if there will ever be any evidence for that. I believe we can be confident that it is an issue that only affects milk,and dairy products.

  8. Naresh Dhakar says:

    Hi Keith,
    I appreciate your dedication in this field from bottom of my heart. I have a query – Can you please let us know if native Indian cow milk have only A2 casein? I have been reading some local research articles where it is mentioned and was curious to know more on it.

    • Keith Woodford says:

      Yes, native Indian cows are 100% A2. The only exception could be if they have a hidden European ancestor somewhere in their genetic history.

  9. Pingback: Got Milk? You Might Got Problems. – Doug Cook RD

  10. Keerthi Kumara M. P says:

    “A1 beta casein causes any particular disease. However, where there is smoke there is almost certainly going to be fire. The results fit perfectly with prior claims relating to digestive function, a range of auto immune conditions, and heart disease ”
    Dear sir
    Now we face to corona virus outbreak , If we consider USA data & South Asia Data on corona virus outbreak we can see unusual number of deaths in USA & UK , I think there is a link with food consuming ( USA & UK people consume A1 milk but Indian people drink A2 milk ) If A1 protein affects to the immune system or reduce the human immunity then we can suspect the A1 protein also contribute to increase the number of people death , Sir Pl look in to this matter & let me know your opinion on this assumption .
    Keerthi Kumara ,
    Sri Lanka

    • Keith Woodford says:

      Dear Keerthi Kumara
      We have no evidence to associate A1 beta-casein with increased susceptibillity to COVID-19. There is a range of factors that affect death rates of COVID-19 between countries and we have to be careful about ascribing these differences to a specific factor.

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