A1 and A2 beta-casein

A1 and A2 beta-casein

Beta-casein is a 209 amino acid protein that makes up about 30% of the total protein contained in milk (1), or roughly 2.5 grams per glass. Due to natural genetic variation, beta-casein can be present as one of two major types, A1 or A2. The single difference between these two types of beta-casein is an amino acid substitution at the 67th residue of the beta-casein protein chain. The subtle structural difference between these two beta-casein types means they are digested differently. The digestion of A1 beta-casein in the gut by the action of digestive enzymes can produce the exogenous opioid peptide called beta-casomorphin-7 (BCM-7) (2-5) (Figure 1). In contrast, A2 beta-casein releases much less and probably minimal amounts of BCM-7 under normal gut conditions (3-6), because for A2 beta-casein “the enzymatic hydrolysis of the Ile66-Pro67 bond does not occur or occurs at a very low rate(2).

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Figure 1: Release of beta-casomorphin-7. Figure adapted from reference (7)

Epidemiological studies have found a correlation between A1 beta-casein intake and the incidence of certain non-communicable conditions (see Figure 2) (8-10). While epidemiological data cannot demonstrate a cause-effect relationship, it does provide population level information regarding exposure to environmental factors and disease outcomes and prompt scientists to investigate important scientific questions arising from observed relationships.

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Figure 2: 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 1990-94 (r=0.92, 95% CI: 0.72-0.97) (p<0.0001). Dotted lines are the 95% confidence limits of the regression line. Figure adapted from reference (9)

Research studies in animals suggest that A1 beta-casein feeding has the potential to stimulate symptoms of digestive discomfort. Two recent animal studies have investigated A1 versus A2 beta-casein on gastrointestinal effects directly (11, 12). Barnett et al. (2014) showed that feeding rodents milk containing A1 beta-casein resulted in significantly delayed gastrointestinal transit time compared to milk containing A2 beta-casein (12), which may affect symptoms of digestive discomfort. In addition, Haq et al. (2013) showed in mice fed a milk free basal diet supplemented with A1 relative to A2 beta-casein that gut inflammation markers were increased significantly with A1 beta-casein whereas A2 beta-casein had no effect relative to control animals (11), effects which a follow up study by the same research group suggest may be mediated by BCM-7 (13). There have been various other animal studies which have examined the effects of BCM-7 on markers of digestive wellbeing. The results from such studies suggest that the opioid activity of BCM-7 is linked to the stimulation of mucous production and thickening from goblet cells in digestive tissue in rodents (14-16).

In human adults, Boutrou et al. (2013) have shown recently that bovine BCM-7 is produced in the intestines following milk casein protein intake in amounts sufficient to elicit a biological action (17). In human infants, studies have shown further that BCM-7 is absorbed into the circulation of formula-fed human babies (18, 19), where there appears to be variation in the ability to eliminate BCM-7 between babies and that this could be due to variable activity of the enzyme needed to break down BCM-7 (19). More recently, Sokolov et al. (2014) have detected BCM-7 in the urine of children (20).

While further research is needed to establish a cause-effect relationship between exposure to BCM-7 and non-communicable disease conditions, there is research to suggest that BCM-7 is linked to various unwanted physiological effects. Notably, Professor Boyd Swinburn (Professor of Global Health and Nutrition , The University of Auckland) in his Report to the New Zealand Food Safety Authority entitled ‘Beta casein A1 and A2 in milk and human health’ (2004) (21) stated:

“……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”.

“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…”.

References:

  1. Walstra P, and Jenness R. (1984). Proteins. In: Dairy Chemistry and Physics. John Wiley and Sons; New York. p. 98-122. ISBN 0471097799. No external link available
  2. 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 [cited May. 2014]. External link.
  3. De Noni I, Cattaneo S, (2010). Occurrence of beta-casomorphins 5 and 7 in commercial dairy products and in their digests following in vitro simulated gastro-intestinal digestion. Food chemistry. 119(2), 560-6. External link
  4. De Noni I, (2008). Release of b-casomorphins 5 and 7 during simulated gastro-intestinal digestion of bovine b-casein variants and milk-based infant formulas. Food chemistry. 110(4), 897-903. External link
  5. Jinsmaa Y, Yoshikawa M, (1999). Enzymatic release of neocasomorphin and beta-casomorphin from bovine beta-casein. Peptides. 20(8), 957-62. External link
  6. Schmelzer C.E, Schops R, Reynell L, Ulbrich-Hofmann R, Neubert R.H, Raith K (2007). Peptic digestion of beta-casein. Time course and fate of possible bioactive peptides. J Chromatogr A. 1166(1-2), 108-15. External link
  7. Woodford K, (2007). Devil in the Milk: Illness, Health and Politics: A1 and A2 Milk. Wellington New Zealand: Craig Potton Publishing. ISBN 1603581022. External link.
  8. Elliott R.B, Harris D.P, Hill J.P, Bibby N.J, Wasmuth H.E, (1999). Type I (insulin-dependent) diabetes mellitus and cow milk: casein variant consumption. Diabetologia. 42(3), 292-6. External link.
  9. Laugesen M, Elliott R, (2003). Ischaemic heart disease, Type 1 diabetes, and cow milk A1 beta-casein. N Z Med J. 116(1168), U295. External link.
  10. Birgisdottir B.E, Hill J.P, Thorsson A.V, Thorsdottir I, (2006). Lower consumption of cow milk protein A1 beta-casein at 2 years of age, rather than consumption among 11- to 14-year-old adolescents, may explain the lower incidence of type 1 diabetes in Iceland than in Scandinavia. Ann Nutr Metab. 50(3), 177-83. External link.
  11. Haq M.R, Kapila R, Sharma R, Saliganti V, Kapila S, (2013). Comparative evaluation of cow β-casein variants (A1/A2) consumption on Th2-mediated inflammatory response in mouse gut. Eur J Nutr. [Epub ahead of print]. External link
  12. Barnett M.P.G, McNabb W.C, Roy N.C, Woodford K, Clarke A.J, (2014). Effects of Dietary A1 and A2 Beta-Casein on Gastrointestinal Transit Time, DPP-4 activity and Inflammatory Status, in Wistar Rats. Int J Food Sci Nutr. [Epub ahead of print]. External link
  13. Haq M.R.U, Kapila R, Saliganti V, (2014). Consumption of β-casomorphins-7/5 induce inflammatory immune response in mice gut through Th2 pathway. J Functional Foods. 8, 150-60. External link
  14. Zoghbi S, Trompette A, Claustre J, El Homsi M, Garzon J, Jourdain G, Scoazec J.Y, Plaisancié P, (2006). Beta-casomorphin-7 regulates the secretion and expression of gastrointestinal mucins through a mu-opioid pathway. Am J Physiol Gastrointest Liver Physiol. 290(6), G1105-13. External link.
  15. Trompette A, Claustre J, Caillon F, Jourdan G, Chayvialle J.A, Plaisancié P, (2003). Milk bioactive peptides and beta-casomorphins induce mucus release in rat jejunum. J Nutr. 133(11), 3499-503. External link.
  16. Claustre J, Toumi F, Trompette A, Jourdan G, Guignard H, Chayvialle J.A, Plaisancié P, (2002). Effects of peptides derived from dietary proteins on mucus secretion in rat jejunum. Am J Physiol Gastrointest Liver Physiol. 3(3), G521-8. External link.
  17. Boutrou R, Gaudichon C, Dupont D, Jardin J, Airinei G, Marsset-Baglieri A, et al. (2013). Sequential release of milk protein-derived bioactive peptides in the jejunum in healthy humans. Am J Clin Nutr. 97(6), 1314-23. External link
  18. Kost N.V, Sokolov O.Y, Kurasova O.B, Dmitriev A.D, Tarakanova J.N, Gabaeva M.V, Zolotarev Y.A, Dadayan A.K, Grachev S.A, Korneeva E.V, Mikheeva I.G, Zozulya A.A, (2009). Beta-casomorphins-7 in infants on different type of feeding and different levels of psychomotor development. Peptides. 30(10), 1854-60. External link.
  19. Wasilewska J, Sienkiewicz-Szlapka E, Kuzbida E, Jarmolowska B, Kaczmarski M, Kostyra E, (2011). The exogenous opioid peptides and DPPIV serum activity in infants with apnoea expressed as apparent life threatening events (ALTE). Neuropeptides. 45(3), 189-95. External link.
  20. Sokolov O, Kost N, Andreeva O, Korneeva E, Meshavkin V, Tarakanova Y, et al., (2014). Autistic children display elevated urine levels of bovine casomorphin-7 immunoreactivity. Peptides. 56, 68-71. External link
  21. 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 [cited May 2014]. External link
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