True or False: There is Good A2 and Bad A1 Casein and Eating the too Much A1 Containing Regular Dairy is Going to Make You Fat, Sick and Insulin Resistant!

"A1 beta-casein is a health risk regular dairy consumers are exposed to." Truth or science fiction even Marvel would be ashamed to propagate?

It sounds like yet another of these Internet humbug myths, but you will hardly believe it, there is actually a recent study investigating the differential effects of A1 vs. A2 beta-casein - and it's not a rodent study (Ho. 2014)!

The scientists from the Curtin University were intrigued by the previous in-vitro and animal studies which suggest that digestion of A1 but not A2 beta-casein affects the gastrointestinal motility and inflammation through the release of beta-casomorphin-7.

In their latest study, Ho, Woodford, Kukuljan & Pal did thus aim to "evaluate differences in gastrointestinal effects in a human adult population between milk containing A1 versus A2 beta-casein." (Ho. 2014)
Before we get to the results let's briefly review why these differential gastrointestinal effects would even be relevant. So let's see what Ho et al. have to say about that:

"Beta-casein is the second most abundant casein type in cows’ milk and comprises ~ 30% of total milk protein. There are two families of beta-casein proteins, known as A1 and A2 beta-casein ‘types’. The A1 type variant arose in European herds from the original A2 type ~ 5000–10 000 years ago from a Proline 67 to Histidine 67 point mutation. In countries that have dairy cows of northern European ancestry, the relative proportions of the co-dominant A1 to A2 beta-casein alleles are typically 1:1 in cows, which then produce the same ratio of A1 to A2 beta-casein in milk. This tends to be lower in breeds from Southern Europe." (Ho. 2014)

As you can see, it's hard to tell, how much A1 "your" milk actually contains. In view of the fact that the A2-only cattle is less productive, you can be pretty certain, though, that the milk you can buy at the supermarket contains significant amounts of A1 beta-casein. Accordingly, there will be a certaion amount of A1 that is converted to the bioactive opioid peptide betacasomorphin-7 (BCM-7) whenever you drink a glass of milk (compared to A1, A2 beta-casein releases much less and probably minimal amounts of BCM-7 under normal gut conditions (De Noni. 1999; Schmelzer. 2007;  Cielinkska. 2012)

So BCM-7 is the villain, here?

BCM-7 is a mu-opioid receptor ligand. It will dock to the mu-opioid receptors which are expressed widely throughout your body - most prominently, obviously, to those in your gut.

If you are looking for something to freak out about, how about homogenization? Try my article "New Research Fuels the Flames on Concerns About Ill Health Effects of Homogenized Milk" | learn more.

From rodent studies we know that the increased transit time and potential downstream on the release and stability of incretin hormones (GLP1, GIP & co), which are involved in the release of insulin and appetite control (Barnett. 2014). In that, the degradatin of GLP1 & co is rather collateral damage that occurs, when the body produces an enzyme to break down the BCM-7 peptides in the gut.

The degradation of "satiety hormones" is yet only one negative side effect Barnett et al. observed. In addition, they found that A1 feeding relative to A2 feeding significantly increased the colonic activity of the inflammatory marker myeloperoxidase by ~ 65%. Unlike the degradation of GLP, GIP & co, this effect which was significantly more pronounced (+207%) in a previous study by Haq et al. (2013), where only A1, in the absence of other molecules from milk was administered, was directly mediated by the activation of the opioid receptors in the gut.

The scientists from the National Dairy Research Institute in India were also able to show that the intestinal interleukin-4 and immunoglobulin E levels as well as the leukocyte infiltration increased with A1 compared with A2 feeding.
BCM-7 has also been reported to alter human intestinal lymphocyte proliferation and promote mucus secretion via MUC5AC mu-opioid receptor activation (Trompette. 2003; Zoghbi. 2006). Now these in vitro studies would be more or less irrelevant, if

"[...] bovine BCM-7 [had not] been detected in the jejunal effluents in humans fed 30 g of casein in amounts compatible with a biological action, which confirms the identification ~30 years earlier of immunoreactive BCM-7 materials in the aspirated small intestinal contents of healthy male adults following milk intake." (Ho. 2014)

Bovine immunoreactive BCM-7 has also been detected in the blood of human infants fed cows’ milkbased infant formula and some Internet sources claim that they are partly responsible for the increased allergy-risk in formula-fed babies. Still, scientists like A.S. Truswell believe that the in-vitro evidence is insufficient and highlight that they "have not yet seen clear evidence that this peptide is released and active in humans in vivo," (Truswell. 2006) citing Svedberget al. (1985) as an example, who found peptides in the human small intestine after the ingestion of 1l of bovine milk that reacted immunologically as if beta-casomorphin 7 but it did not show opioid activity or behave  chromatographically as authentic beta-casomorphin-7.

With its opiod-receptor interactions there is still a plausible mechanism that could explain some, but not all of the often cited ill health effects. A human study which assessed whether A1 relative to A2 beta-casein-containing milk imparts different gastrointestinal effects in human adults, however has not been conducted before.

It's time for real human data, now!

It was thus about time for Ho et al. to approach this issue by investigating the the gastrointestinal effects of dietary A1 versus A2 beta-casein-containing milk in adults using subjective and objective measures of gastrointestinal performance.

In an 8-week cross-over study, 12 men and 29 women (19–68 years) from Perth, Western Australia, were randomly assigned to one of two groups for 2 weeks, following a 2-week dairy washout in which rice milk substituted dairy milk (A1) milk containing beta-casein of A1 type (n= 21); or (A2) milkcontaining beta-casein of A2 type (n= 20). Exclusion criteria were as follows: (1) milk allergy; (2) diagnosed lactose intolerance; (3) pregnancy/ lactation; (4) cardiovascular events in the last 6 months; (5) opioid consumption; (6) antibiotic treatment in the previous 8 weeks; and (7) immunosuppressive medication or anti-inflammatory drugs in the 4 weeks before screening. Before crossing over to part II of the study, the participants underwent a second 2-week dairy.
During the 2-week A1 and A2 beta-casein interventions, participants were instructed to consume 750 ml/day of their allocated milk (containing ~ 7.5 g of either A1 or A2 beta-casein) over the day and to avoid all other dairy products. The A1 and A2 milk were both standardised to the following nutrition
profile per 100 ml: energy 189 kJ, total protein 3.1 g, total fat 2.5 g and lactose 5.2 g; no other known differences existed.

"Proteome Analysis Facility, Macquarie University, Sydney, NSW, Australia) of the A1 and A2 milk showed that the A1-type beta-casein proportion of total beta-casein was 499% in the A1 milk and⩽0.5% in the A2 milk."

The milk was processed and packed in identical 1-l UHT plain packages (blinding participants and the investigator to each milk intervention) by Pactum Australia Pty Limited, Taren Point, NSW, Australia, to ensure successful blinding.

The assessments, the scientists did included anthropometry, diet and physical activity measurements, a test for markers of inflammation in the gut, and subjective recording of gastrointestinal symptoms. The tummy aches, flatulence, stool consistency, etc. as well as the general food intake and compliance, i.e. "did I ingest my milk, or didn't I" were recorded in daily logs. An analysis of these logs revealed that the

[...m]ean compliance with the A1 and A2 diets was 96.2% (±5.3) and 96.4% (±6.6), respectively. Greater than 100% compliance stems from some participants consuming extra study milk in tea/coffee/food." (Ho. 2014)

Significant between group differences for milk, energy, fibre or calcium intakes during the intervention were not detected. The latter could not be said for the quality of the stools: As you can see in Table 1 there were significant differences between the stool quality during the A1 and A2 phase of the study.

Table 1: . Bristol Stool Scale analyses of stool consistency (mean±s.e.m. | Ho. 2014)

Interestingly, a subgroup analysis revealed that these differences were significant only in women and the previously mentioned subgroup of initially 10 subjects who claimed that they were milk intolerant.
Against that background, it's a at least surprising that the values of gastrointestinal discomfort were numerically higher on the A1 diet, but not significantly elevated - even for the eight remaining milk intolerant individuals, for whom the mean A1 values were considerably higher than A2 values for bloating (61% higher), abdominal pain (38% higher) and voiding difficulty (83% higher), statistical significance was not detectable due to the the small participant numbers in the selfidentified milk-intolerant group.

Among the correlates of the gastrointestinal symptoms the scientists evaluated, only the absence of the A1-exclusive correlation between loose stools and abdominal pain appears worth mentioning. Loose stools, which were less frequent in the A2 group, could thus be a first indicator for what I would like to call A1 intolerance. Whether this is a direct result of the previously discussed opiod-receptor interaction is yet uncertain. As Ho et al. point out, the loose stools could also be the result of

"[...] greater opportunities for food fermentation and hence digestive discomfort within the gastrointestinal system." (Ho. 2014)

This effect would that occur in response to the initial increase in gastric transit time due to A1 consumption, not as a direct consequence of opiod-receptor interactions. Assuming that the "fermentation hypothesis" is correct, the difference between "milk tolerant" and "milk intolerant" subjects could eventually come back to something as simple as having the "wrong" gut bacteria. Corresponding evidence that probiotic supplements can sooth the pro-inflammatory reaction in milk intolerant subjects comes from a study by Pelto et al. who observed that probiotic bacteria down-regulate the milk-induced inflammatory response in milk-hypersensitive subjects but have an immunostimulatory effect in healthy subjects (Pelto .1998).
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