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Got claudins?

 

Spend anytime visiting nutrition-oriented blogs and you quickly discover that the topic of dairy consumption elicits strong opinions. Dairy, in all its forms, has been variously blamed for heart disease, cancer, autism, diabetes, obesity, Kim Kardashian’s fame…well pretty much everything.

Some caution against the consumption of dairy by pointing to the fact that humans are the only animals to consume milk past weaning. Others suggest that as a “Neolithic food”, it’s not fit for human consumption.

I remember being told this once by a person of the “Paleo-diet” persuasion in-between sips of their cocktail. The lack of archeological evidence for vodka distilleries in the Paleolithic seemed to have escaped the notice of this modern-day alcohol-imbibing “caveman” warning against the “evils” of dairy.

Today I want to review two studies that found that dairy proteins, both whey and casein, strengthen gut-barrier function.

Before I begin, I need to mention that neither study was done in humans. The first was an in vitro study, meaning it used cultured human-epithelial cells and was conducted in a lab. The second was a study done in rats.

It should go without saying that what is true for an in vitro or rodent study is not always applicable to humans. Hopefully, this will soon change as more and more foods are tested for their effects on intestinal permeability in people. Nevertheless, both whey and casein proteins are found in human-breast milk and can be expected to have similar effects in us as they do in other mammals.

Of all classes of tight-junction proteins, claudins are the most important for maintaining intestinal integrity in mammals. Mice bred to lack these proteins die within 24 hours of birth. (1)

As of this writing, science has identified 24 different claudin proteins. The word claudin, by the way, is derived from the Latin word “claudere” which means “to close.”

 

Courtesy: Exercise regulation of intestinal tight junction proteins

Courtesy: Exercise regulation of intestinal tight junction proteins

 

To refresh everyone’s memory, when I talk about endotoxemia as a result of increased intestinal permeability, I am not talking about the transport of nutrients across the intestinal epithelial cell. This process, known as transcellar transport, is totally natural and a sign of a properly functioning small intestine.

As I explained in part three of my heart disease series, gut pathogens that happen to hitch a ride on chylomicrons formed as a result of digesting long-chain fatty acids are neutralized by these same molecules. They are then safely excreted from the body assuming a healthy liver and the absence of a bile obstruction.

However, transport between epithelial-gut cells, or paracellular transport, should only be limited to water, electrolytes and some trace nutrients. When tight junctions are disassembled for whatever reason (gluten, cough, alcohol, cough, cough) whatever happens to be in the lumen now has the ability to breach the gut wall and spill into the portal vein.

Once that happens, it’s the poor over-worked liver that receives the full brunt of this antigen load. How well it handles this assault and whether those antigens enter systemic circulation depends on how bad the endotoxemia is and the overall health of this organ.

Not all claudins maintain intestinal integrity, however. Some claudins seal the gut (are pore-sealing), while others make it more permeable (are pore-forming).

Claudins -1, -3, -4, -5 and -8 have been classified as pore-sealing proteins. You want these claudins up-regulated along the length of your digestive tract to ensure a tight seal against the contents of your gut.

Claudin-2, however, is a pore-forming junction protein. The expression of this claudin increases intestinal permeability.

In colonic biopsies performed on patients with Crohn’s disease, claudin-2 is strongly elevated. Meanwhile, pore-sealing claudins -5 and 8 are down-regulated in this disorder. (2)

Ulcerative colitis is another inflammatory bowel disease characterized by up-regulation of claudin-2. So too collagenous colitis where increased expression of this protein is associated with a low expression of pore-sealing claudin-4. (3)

It should surprise none of you that beneficial bacteria and their metabolites affect tight junction proteins through numerous mechanisms. Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus acidophilus, Bifidobacterium breve, Bifidobacterium bifidum and Bifidobacterium infantis have all been found to maintain or strengthen gut-barrier function and protect against endotoxemia. (4) (5) (6) (7)

Food components can also affect tight-junction integrity as you’ve already learned by reading this blog. They can do so either directly by affecting zonulin expression or by encouraging the growth of gut pathogens. Some food constituents, like gluten, do both.

Returning to dairy—milk, whey protein and whey protein concentrate—all contain high levels of transforming growth factor beta (TGFβ). TGFβ is a type of anti-inflammatory cytokine. This family includes a subfamily named transforming growth factor beta 1 (TGFβ1).

These proteins have important properties that inhibit the initial growth of cancer cells and induce their death or apoptosis. They are also involved in regulating immune function. TGFβ1 is found in highest levels in the whey fraction of human and cow’s milk. Breast milk naturally has a very high level of TGFβ1.

In an in vitro study published in 2011, whey protein concentrate rich in TGFβ1 increased the expression of pore-sealing claudin-4 without affecting claudins-1, -2, -5, -7 or occludin. (8) By doing so, it increased intestinal barrier function. As these researchers noted:

“Taken together, the present study describes the molecular mechanisms of barrier protection via expression regulation of the tight junction protein claudin-4 in response to TGFβ as present in whey protein concentrate from bovine milk. This identifies a mechanism of the curative effect of milk components that have for a long time been considered to protect intestinal function. In this manner, such milk preparations may be considered as functional food and may be tested as part of multimodal therapies, e.g. in immunonutrition for inflammatory bowel disease patients, in the future.”

 

Courtesy: Emerging Health Properties of Whey Proteins and Their Clinical Implications

Courtesy: Emerging Health Properties of Whey Proteins and Their Clinical Implications (9)

 

This graphic illustrates the many benefits of whey protein found as a result of both in vitro and animal studies. I believe many of these benefits derive from this protein’s ability, along with beneficial gut flora, to reduce the occurrence of endotoxemia.

However, whey isn’t the only dairy protein under current study for its effects on the intestinal wall. A second study has also hinted at casein’s ability to strengthen gut-barrier function in a rodent model. (10) In this study, rats genetically bred to be susceptible to the development of autoimmune type 1 diabetes were placed on either a high-casein or standard plant-based diet.

The high-casein diet was a modified AIN-93G rodent chow and contained the following: 200 g/kg casein, L-cysteine, corn starch, sucrose, soy-bean oil, cellulose, mineral mix, vitamin mix, choline bitartrate and butylated hydroxyanisole antioxidant.

The ingredients in the plant-based chow were: wheat, meat meal (80% sterilized), yellow dent corn, whole oats, wheat middling’s, alfalfa, soya oil, dried yeast, dicalcium phosphate, calcium carbonate, NaCl, dl-methionine, vitamins and trace elements.

Do be sure to note that wheat was the number-one ingredient in the plant-based chow and that sugar (sucrose) was not a constituent of this diet.

Levels of lactulose and mannitol were measured in the urine of these rats to detect intestinal permeability. Animals on the high-casein (HC) diet had lower levels of intestinal permeability than their cohorts. Serum zonulin levels, a marker for intestinal permeability, were also lower in the rats fed the high-casein diet.

Rats on the HC diet were found to have increased levels of pore-sealing claudin-1 and reduced expression of pore-forming claudin-2. Because of this, the incidence of autoimmune type 1 diabetes in the high-casein rats was 50% less than in the gluten-fed animals.

The differential effect seen in this study has several possible explanations.

A high-casein diet has been seen to increase mucin levels (mucus) in the guts of diabetes-prone rats. (11) Doing so decreased their intestinal permeability and lowered insulin levels. The mucosal layer is an important physical part of our gut barrier and along with beneficial bacteria prevents a “leaky gut”.

Another finding was that the high-casein diet increased levels of two anti-inflammatory cytokines: interleukin 10 (IL-10) and the above-mentioned transforming growth factor beta 1. By doing so, the HC diet suppressed inflammation in these rodents which would have inhibited intestinal permeability.

Finally, the presence of gluten in the plant-based rodent chow had obvious negative impacts on the tight junctions of those animals. As the authors of this paper pointed out:

“Food components and intestinal bacteria can affect the integrity of the intestinal barrier. Recently, Mojibian et al. demonstrated that ~50% of established type 1 diabetes patients have T cell responses against wheat polypeptides. These results indicate that wheat might be a major dietary antigen capable of inducing type 1 diabetes. An important question raised by the Mojibian study is why in ~50% of type 1 diabetes patients a wheat polypeptide-specific response is found. Interestingly, studies by our group and others have shown that also ~50% of type 1 diabetes patients have intestinal barrier defects. Although Mojibian et al. did not investigate whether the wheat-specific T cell responses correlated with impaired intestinal barrier function, it is reasonable to hypothesise that impaired intestinal barrier function leads to an increased passage of intestinal diabetogenic antigens (e.g. wheat peptides, bacterial agents) that induce the autoimmune cascade typical of type 1 diabetes. To prove this hypothesis, further investigation of the relationship between intestinal barrier function and immune responses against intestinal antigens and beta cells in type 1 diabetes patients will be required.”

And you probably thought I was being unnecessarily alarmist about gluten, didn’t you?

That milk, whether from a human or other warm-blooded animal, has these properties should not be at all surprising. As the first food a mammal ingests after birth, it would be expected to include nutrients that not only nourish it and its gut flora, but also strengthen gut-barrier function. After all, without a healthy gut wall it doesn’t really matter how nutritious mother’s milk or any other food is now does it?

Should these studies be proven applicable to the expression of tight-junction proteins in humans, and I’m pretty sure they will be, the recommendation to eliminate dairy from the diet is a tad bit ill-conceived. Of course, this assumes the absence of verifiable dairy allergies. However, the presence of a dairy allergy is itself a symptom of increased intestinal permeability due to gut dysbiosis and other dietary components, not likely its cause.

The formation of opioid peptides from consuming A-1 beta-casein dairy must be taken into consideration in cases of autism-spectrum disorders, constipation and gut dysbiosis as I’ve mentioned before. It would be wise, therefore, to seek out A2 beta-casein dairy while healing and sealing the gut. Once dysbiosis is a distant memory, the consumption of even A1 beta-casein is likely to not pose a problem for most.

Disentangling whether gluten or dairy proteins are causing health problems is a major confounder in observational studies and anecdotal accounts implicating dairy. The reality is that the consumption of dairy and gluten-grains very often goes together: cheese and crackers, mac and cheese, cookies and milk, cake and ice cream, beer and nachos, grilled cheese sandwiches, pizza, wheat cereal and milk, butter and toast, cheeseburger and bun, etc., etc., etc.

I would hypothesize that the high dairy consumption in the West is probably protective against the permeability-enhancing effects of gluten. For example, ricotta, a cheese high in whey protein and a common ingredient of lasagna, may make that dish far healthier than would otherwise be the case.

Pointing out that Asian cultures are not big consumers of dairy and that this somehow “proves” it’s hazardous to health holds very little water with me. The reality is that the traditional grain eaten in large parts of Asia is rice, a grain that does not have known negative effects on gut-barrier function.

This difference may be largely accountable for the variance in health outcomes between Eastern and Western populations. Unfortunately, those differences are rapidly disappearing due to the increasing substitution of wheat for rice as the staple grain of these societies.

For those of my readers experiencing gut issues, especially inflammatory bowel disorders like ulcerative colitis or Crohn’s disease, you may be better served by ignoring the naysayers and supplementing your diet with high-quality dairy, or at a minimum, with whey protein. The latter option may be best if lactose intolerance or casein allergy is an issue for you.

There are legitimate medical rationales for avoiding dairy including acute or latent allergies. Nonetheless, avoiding it because it’s a “Neolithic” food or because of the results of hopelessly confounder-prone population studies are not good reasons for doing so. Avoidance may be far more harmful to the integrity of your gut than you can imagine, especially if gluten, plant lectins, alcohol, refined fructose or omega-6 oils remain part of your diet.

 

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