Tag Archives: wheat

Gluten Free | The Paleo Diet

Last week, The New York Times published an op-ed by Roger Cohen, its International Affairs and Diplomacy correspondent, regarding…wait for it – gluten!1 Has gluten become the nefarious “sticking point” that underlies our most critical diplomatic issues? Or was this just another of Cohen’s haughty rants against people who purchase organic food, implement health-optimizing diets, and keep abreast of nutrition science research? Spoiler alert – it’s the latter.

The gist of Cohen’s latest article, “This Column is Gluten-Free,” is that wheat has gotten a bad rap, despite graciously feeding the world for the past 12,000 years. Cohen acknowledges that gluten is harmful for the roughly 1% of the population that has celiac disease, but what about the remainder of the estimated 30% of Americans who are cutting back on gluten or going gluten-free?2

Does non-celiac gluten sensitivity (NCGS) exist? Is there evidence that gluten can be harmful for the general population? According to Cohen, people who eschew gluten (celiac patients excluded) are “self-indulgent” narcissists with imaginary food intolerances. “Having a special dietary requirement,” Cohen asserts, “is one way to feel special in the prevailing ‘me’ culture.”

Narcissism seems to be Cohen’s favorite buzzword when describing nutrition-motivated people, particularly those who buy organic food and avoid gluten. In this capacity, he uses the n-word no less than three times in his latest article, and in a previously article, he scolds the “affluent narcissism” of the upper middle class, people who purchase organic food while the poor “get a lot more nutrients from the two regular carrots they can buy for the price of one organic carrot.”3

This gets to the crux of Cohen’s ethos. He takes issue with individualism and self-determination, preferring a social structure whereby the balance of power is significantly tilted toward the state. In yet another recent article, he comments on a Pew Global Attitudes survey for which Americans and Europeans were asked which is more important,

  1. “freedom to pursue life’s goals without state interference,” or
  2. “state guarantees that nobody is in need.”

Much to Cohen’s dismay, 58% of Americans say the former is more important (compared to 62% of Europeans who prefer the latter).4 He then suggests the government should be more empowered to dictate how people eat, starting with a “coordinated policy action” designed to reduce sugar consumption, but where would it end?

What if the government decided that gluten is only dangerous for those with celiac disease? Could it outlaw a generalized form of “gluten-free” labeling? After all, because the US government supports GMO foods and deems them absolutely safe, it has repeatedly thwarted legislative attempts to implement mandatory GMO labeling. Not surprisingly, Cohen also strongly supports GMO foods:

“To feed a planet of 9 billion people,” he insists, “we are going to need high yields not low yields; we are going to need genetically modified crops; we are going to need pesticides and fertilizers and other elements of the industrialized food processes that have led mankind to be better fed and live longer than at any time in history.”5

Feeding the poor is a noble goal, even with subsistence-level nutrition, but so is health optimization for individuals, which is a primary goal of nutrition science research. These goals, however, are not incompatible; they are complementary. Nevertheless, Cohen’s steadfast resolve to restore wheat’s “amber waves” reputation prevents him from critically assessing and/or acknowledging the scientific research on gluten, the dangers of which extend far beyond just celiac patients.

Just last month, for example, researchers at the National Institutes of Health published a randomized, double-blind, placebo-controlled, cross-over trial on people who don’t have celiac disease but believe themselves to be gluten sensitive. The results? “The severity of overall symptoms increased significantly during 1 week of intake of small amounts of gluten, compared with placebo.”6

For further reading on the science behind how gluten can damage the gut and compromise health, check out Trevor Connor’s excellent 5-article review, “The Wheat Series.” Nutrition is always vulnerable to politicization, but rather than choosing sides, why not seek mutually beneficial solutions to complex, interdependent challenges? Being kind and respectful also helps immensely (leave the diet-shaming for the narcissists).

References

1. Cohen, R. (October 19, 2015). This Column is Gluten-Free. The New York Times. Retrieved from http://www.nytimes.com/2015/10/20/opinion/this-column-is-gluten-free.html?_r=0

2. Strom, S. (February 17, 2014). A Big Bet on Gluten-Free. The New York Times. Retrieved from http://www.nytimes.com/2014/02/18/business/food-industry-wagers-big-on-gluten-free.html

3. Cohen, R. (September 6, 2012). The Organic Fable. The New York Times. Retrieved from http://www.nytimes.com/2012/09/07/opinion/roger-cohen-the-organic-fable.html

4. Cohen, R. (August 5, 2015). Incurable American Excess. The New York Times. Retrieved from http://www.nytimes.com/2015/08/07/opinion/roger-cohen-incurable-american-excess.html

5. Cohen, R. (August 5, 2015). Incurable American Excess. The New York Times. Retrieved from http://www.nytimes.com/2015/08/07/opinion/roger-cohen-incurable-american-excess.html

6. Di Sabatino, A., et al. (September 2015). Small Amounts of Gluten in Subjects With Suspected Nonceliac Gluten Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. Clin Gastroenterol Hepatol, 13(9). Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/25701700

Wheat | The Paleo Diet

Click Here to Start The Wheat Series from the Beginning!

It’s one of the most commonly used analogies in existence and it’s about a game that few want to play. A revolver is loaded with a single bullet. The hapless players take turns putting the gun to their heads and pulling the trigger. The analogy is often used to make a point about the high stakes of luck. Eventually someone gets a loaded chamber and pays the ultimate price.

There is a second side to the analogy, however that is frequently overlooked. Regardless of whether you have extremely good or bad luck, you first have to willingly pull the trigger.

We’ve known for a while that most chronic diseases such as cancer, autoimmune disease, and heart disease have a genetic component.1 – 10 Genetics are the loaded bullet that we sadly have no control over.

For celiac disease, the “bullet” is a genetic variant in HLA-DQ.11, 12 However, a large number of people with the variant never express the disease. Further, those who do develop the condition usually resolve it by removing gluten from their diet.13, 14 In other words, the bullet might be in the chamber, but often the gun is never fired.

Environmental factors ultimately pull the trigger.

In the first four parts of this series we talked about how wheat (and to a degree other gluten-containing grains such as rye and barley) is highly effective at dysregulating the immune system of our guts. In fact, it’s the only food we know of that affects all three pathways of dysregulation:

  1. Opening up the tight junctions of our gut (Part 2)
  2. Excess and chronic bacterial stress (Part 3)
  3. Harmful dietary antigens (Part 4)

In this final part, we’ll talk about how the resulting chronic inflammation leads to a pathological state that essentially “pulls the trigger” on disease. But just as importantly, we’ll discuss how there has to be a bullet in the chamber first. The genetic susceptibility has to be there.

It’s Not So Easy to Pull the Trigger

Our genetics have not changed in the last 100 years. Yet, chronic disease such as autoimmune conditions and cancer have risen dramatically. Faster than rate of population growth.

In other words, going with our analogy, the number of bullets hasn’t changed, but for some reason the trigger is getting pulled a lot more often. Which is surprising considering no one wants to pull it.

Imagine for a minute what it takes for a person to get to the point where they will voluntarily put a gun to their heads. None of us handed a revolver and told we have a five in six chance would exclaim “sure, those sound like good odds.”

From what little we understand, Russian Roulette players essentially have to build up to it, engaging in other risky behavior, and slowly desensitizing themselves. As it turns out, a lot of behavior altering substances help too.15

Likewise, our bodies have a lot of defenses to avoid ever pulling the trigger on disease, even when the bullet is there.

So, while we hopefully made the case in the previous four parts that wheat is not good for us, one piece of bread isn’t going to give you cancer. Despite all the dysregulation of our immune system caused by wheat, it still takes a lot to build up to the point of disease.16, 17

Building Up to It…

In fact, as we discussed in Part 1, all the inflammatory processes activated by wheat are both normal and necessary processes designed to deal with regular bacterial stress. Mice breed without these inflammatory responses suffer severe tissue damage and wasting disease.18, 19

Even the temporary shift in the balance between two critical immune cells – Tregs and TH17 cells – is a natural response to this inflammation. Let’s explore these two cells a little more.

In a healthy state, Tregs dominate. Their role is to suppress the immune system20 – 24 preventing it from damaging our own bodies. People unfortunate enough to have dysfunctioning Tregs suffer severe autoimmune diseas.25

TH17, on the other hand, have a murkier and less benign role. Only discovered in 2006, they solved an important puzzle for researchers. Scientists knew that T cells were involved in many conditions but none of the known T cells at the time fully explained disease development.26

With the discovery of TH17, they had their answer.26, 27

Proving to be highly inflammatory cells, TH17 effectively explained the damage in a multitude of chronic diseases16, 28 – 31 such as asthma,32 heart disease,33, 34 and most autoimmune conditions30, 35 including celiac disease,36, 37 type I diabetes,38, 39 Crohn’s disease,40, 41 rheumatoid arthritis,31, 42 and multiple sclerosis.43

A question remained, however: Why would our bodies produce such a self-destructive cell?

The reason lies in their role. It was believed that TH17 cells evolved to deal with harmful bacterial infections and effectively handling the invasion means doing some damage to our own bodies.19, 44, 45

This damage seems to be acceptable to our bodies and even part of a healthy immune response as long as one essential condition is met – the shift towards TH17 dominance is short-lived and ends. Once an infection is dealt with and the resulting inflammation quiets down, TH17 cells die off and Tregs return to dominating our immune system.24, 46

So what happens if the inflammation doesn’t end?

According to one emerging theory, the result is an out-of-control pathogenic form of the TH17 cell.10, 23, 24 In other words, if normal bacterial stress causes a little risky behavior by inciting beneficial TH17, chronic inflammation causes the buildup that leads to the pathogenic TH17 putting the gun to our heads and pulling the trigger.

Chronic Inflammation – Putting the Gun to our Heads

The diagram below shows the different responses between normal and chronic inflammation.30

Chronic Inflammation | The Paleo Diet

Kamada, N., et al., Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol, 2013. 13(5): p. 321-35.

Let’s explore this destructive shift a little more closely. Bear with me – this gets technical.

Under normal inflammation, the number of Treg cells increase alongside the TH17 cells allowing Tregs to continue controlling TH17’s destructive potential and maintain some balance.30, 47

But in chronic inflammation, a dramatic shift occurs. More and more innate immune cells such as dendritic cells and CD14+ macrophages (explained in Part 3) are activated or recruited to the digestive immune system.17, 28, 48, 49

Over time, these cells change the chemical milieu of the gut to one that is high inflammatory. Il-23 is released which both promotes the destructive form of TH17 and inhibits Tregs.27, 47, 50, 51 Newly recruited CD14+ macrophages also suppress Tregs.52

In fact, it gets worse. The chronic inflammation causes Tregs to “flip” and start behaving like TH17 contributing to the inflammation instead of preventing it.47, 52, 53

The result is that chronic inflammation breaks the Treg/ TH17 balance. Treg lose their ability to control the immune system and TH17, now uninhibited, take on a more destructive form traveling from the gut45 throughout the body pulling the trigger:30

Gut Microbiota | The Paleo Diet

Kamada, N., et al., Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol, 2013. 13(5): p. 321-35.

This is the point where you may want to remind me that this is the fifth part in a series about wheat. Where does wheat come into all of this?

Wheat, as we’ve shown in the previous parts, creates the chronic inflammation that sets off this cascade. In fact, in one study of mice, that tested many dietary antigens, wheat was the only one that could activate inflammatory TH17 cells.54

Put simply, wheat sets in motion the build-up that causes our bodies to ultimately put the gun to our heads and pull the trigger.

Why Aren’t More Guns Going Off?

The very sobering thought is that the chronic inflammation, which wheat is so effective at creating (in fact it took three parts to explain all the ways wheat can cause it,) appears to be common to everyone.17, 20, 55

So why aren’t we all sick?

This is where we need to flip things around and remember there are two parts to the Russian Roulette analogy. Wheat causes our immune system to put the gun to our heads and pull the trigger, but there still needs to be a bullet in the chamber. The genetic susceptibility has to be there.

Sure enough, a genetic susceptibility to chronic inflammation has been identified in many conditions. Often taking the form of a hyper-sensitivity to inflammation or a failure of the Treg system to suppress it.

CD14+ macrophages appear to be particularly potent in rheumatoid arthritis.56 Celiacs are hyper-sensitive to Il-15 – one of the key proteins used by wheat to produce inflammation.3 Much higher levels of inflammatory CD14+ macrophages exist in the guts of people with Irritable Bowel Disease (IBD).57 IBD sufferers also appear to be more responsive to IL-23.29 In type II diabetes, the immune cells that destroy the pancreas exist in healthy and afflicted subjects, but Treg cells appear to be less functional in diabetics.1, 2

Making a further case for the importance of genetics, people with one of these conditions are often more susceptible to the others.58-63

Still, There Are a Lot of Bullets…

The need for a “genetic bullet” in order for a disease to materialize has led many to breathe a sigh of relief. An example is the recent Washington Post article “For many, gluten isn’t the villain it gets cracked up to be.”

But the fact is that there are many chronic disease and they are all on the rise. A lot more guns are actually going off now.

Recent research is showing more and more that inappropriate chronic inflammation is at the heart of almost every “disease of civilization” including cancer,64, 65 metabolic disorders,66, 67 Alzheimer’s disease,68 most autoimmune conditions,30, 35 and heart disease where aberrant macrophages (immune cells) form the atherosclerotic plaques.69, 70

That amounts to a whole lot of genetic bullets.

While the research is still small, several of these conditions including celiac’s disease, diabetes, and     IBD are improved when wheat is removed from the diet.13, 14, 71 – 73

So feel free to do as the Washington Post article says, eat your bread, and trust your luck that the chamber is empty. But with that many potential bullets in the revolver and chronic inflammation – so effectively produced by wheat – ready to pull the trigger, I’m personally going to avoid putting the gun to my head.

References

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  37. Castellanos-Rubio, A., et al., TH17 (and TH1) signatures of intestinal biopsies of CD patients in response to gliadin. Autoimmunity, 2009. 42(1): p. 69-73.
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  40. Elson, C.O., et al., Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology, 2007. 132(7): p. 2359-70.
  41. Brand, S., Crohn’s disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn’s disease. Gut, 2009. 58(8): p. 1152-67.
  42. Hirota, K., et al., Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med, 2007. 204(12): p. 2803-12.
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The Wheat Series Part 4: Home Invasion | The Paleo Diet

Did you miss The Wheat Series Part 1: Wheat and the Immune System? Read it HERE.
Did you miss The Wheat Series Part 2: Opening the Barrier to Poor Gut Health? Read it HERE.
Did you miss The Wheat Series Part 3: Setting Off the Bacterial Alarms – With or Without the Bacteria Read it HERE.

Nothing is scarier than someone invading your home. You’re nearly asleep when you hear the sound of something rustling downstairs. Instantly you’re awake and your internal alarm bells go off. You grab the phone. Fortunately the police are nearby and arrive almost instantly. They’ll catch the invader. You have nothing left to fear. Or do you?

The police enter the darkened house to a confusing scene. Your teenage son, sneaking home from the party you told him not to go to, has stumbled into the unknown invader. Meanwhile, your partner has entered the other side of the room carrying a baseball bat. The police can just make out three figures in the dark. Several seem armed and one may be a hostage. An officer draws her gun, but who does she point it at?

Sadly, it’s not always a happy ending. Innocent people are killed in their own homes all too often.

While a home invasion is something most of us will hopefully never experience, dealing with invaders is something our bodies have to handle thousands of times each day. And just like a thief entering your house, it would seem the job of identifying the invader – bacteria and viruses – should be a simple task. But it’s not.

The immune system – the police of our bodies – has to deal with equally dark and confusing scenarios as it tries to differentiate dangerous invaders from our own cells, beneficial microflora, and food.1-3

Fortunately, it has evolved remarkably complex systems that make it very good at determining which is which.

One food however is even better at breaking in, turning out the lights, and making the police point the gun in the wrong direction.  Wheat.

In Parts 1, 2, and 3 of this series on wheat, we talked about how wheat affects the three things that can cause the digestive immune system to dysfunction. The first was increased permeability (Part 2), the second was excess bacterial stress (Part 3). The third is the subject of this post – harmful dietary antigens.

ANTIGENS – IDENTIFYING THE INVADER

Antigens are critically important to our immune defenses. In fact, without them, most of our immune system wouldn’t be able to function. Which begs the question – what exactly are antigens?

They are just molecules. And not really any special type of molecule. Antigens exist in everything – bacteria, viruses, our food, even our own cells. As long as our immune cells can bind to it and identify it, it’s an antigen.4

Certain cells in our immune system, called antigen presenting cells (APCs), travel around our bodies “sampling” everything they encounter. They aren’t particular – they’re just as likely to check out our own cells as a foreign bacterium. They chew everything they sample into small molecules and present these antigens to the brains of our immune system – T Cells.4

T Cells are trained from birth not to respond to our own unique self-antigens which makes them remarkably good at identifying anything foreign. Together, T Cells and APCs determine when an antigen isn’t self and more importantly if it’s something to be worried about.5

Think of an antigen as an ID card. APCs and T Cells are the police hunting through the house for anyone who doesn’t belong. The more hot-headed APC likes to slam anyone it encounter up against the wall and takes their ID. It’s the T Cell who looks over their identification and decides if they belong or not. It’s the misfit buddy cop movie of our bodies.

The problem is, just like in the movies, ID cards are easy to fake. Some viruses have evolved the ability to mimic our own antigens in an attempt evade detection.6, 7

And like your daughter’s boyfriend who tends to sneak through the window at night, not everything from outside is bad (though some fathers reading this may be thinking “shoot him.”) Beneficial bacteria in our gut are foreign, but we’ve learned to live in synergy with them.2, 3, 8 Likewise, all food is technically foreign, but an immune response to we eat would lead to debilitating allergic reactions and worse.9-11
To deal with this extra level of complexity, our immune systems have developed two sophisticated “interogation” techniques – co-stimulation and oral tolerance.

CO-STIMULATION (OR THE SECOND SIGNAL)

Just identifying an antigen as foreign actually isn’t enough for a T Cell to start an immune response. The T Cell must also receive an activating signal from the APC as it presents the antigen. The APC gives this second signal when it has been exposed to a large amount of the antigen or if the body is in an inflamed state.5, 12-15

It’s the equivalent of the T Cell asking the APC “I don’t recognize this guy, should I draw my gun?” Surprisingly, the tough guy APC generally replies “What this wimp? Nah I can take him.”

ORAL TOLERANCE

This is a fancy term for not reacting to food. A special type of APC, called dendritic cells (DCs), specializes in reaching into the gut to sample food particles and microflora. Most of the time it presents the antigens with the message: “This is food. Don’t do anything.”1, 12, 14 DCs work in conjunction with a special T cell called T Regulatory (Treg) cells that respond to self-antigens instead of foreigners. But unlike other T cells, when activated, Tregs supress the immune system.12, 16-18

These two cells are the police movie equivalent of the by-the-books pencil-pushers who constantly tells the loose cannon to holster his gun. Fortunately, in our bodies, the pencil-pushers are in control most of the time.17

The image below shows the antigen identification system in action. Plasma cells, macrophages and DCs are all APCs. As you can see, in the healthy gut, Tregs dominate.19

WHEAT: THE MASTER CRIMINAL

For the rest of this post we’ll talk about how wheat is essentially a “master criminal” able to flip our antigen identification system on its head. But unlike a virus, wheat doesn’t break the system to try to evade detection. Instead it intentionally sets of the alarms and provokes the immune system to draw its guns. Tragically it’s also very good at getting immune cells to fire on the wrong target.20

THE LOCK PICKING PICKPOCKET

Part 2 of this series explained how wheat effectively opens the tight junctions of our gut allowing bacteria, large molecules and gliadin from wheat itself to enter the body.21-24

But that’s not the only way wheat breaks in.

A protein in wheat called Wheat Germ Agglutinin (WGA) is very good at binding to the cells in our digestive tract and passing right through them into our blood stream.13, 25, 26 WGA can also bind other particles. So not only can it gain entry into circulation, but it can carry antigens from the gut with it.27, 28

THE POLICE PROVOKER

Above, we discussed how the immune system doesn’t automatically respond to foreign antigens. It first needs a co-stimulation before drawing its guns. We also covered the two things that cause APCs to provide this second signal.

The first was exposure to a large quantity of antigens. By “picking the locks” to the house, wheat essentially flings open the doors allowing a huge flow of antigens from the gut into the body.

The second thing that gets APCs to provide the co-stimulation is inflammation. In Part 3 of this series, I explained how wheat tricks the body into believing it is under perpetual bacterial stress.29-33 This creates a constant inflammatory state that causes the once suppressive DCs to flip and start activating the immune system.34, 35 Other APCs follow suite.30, 32, 36-39

In other words, the once tolerant “pencil-pusher” cops of the immune system become gun happy in a way that would make Arnold Schwarzenegger cringe.13

In short, wheat ensures there’s a co-stimulation. Wheat also breaks tolerance:

WGA is able to enter the body bypassing all the mechanisms of oral tolerance.25, 28 So, the first time WGA and the food antigens bound to it are exposed to the immune system is in circulation where the response is almost always inflammatory.

Worse, in multiple studies of wheat’s effect on mice and humans, wheat reduced the levels of Treg (the immune-suppressors) in favor of a type of T Cell called Th17.29, 34, 40 We’ll explore this shift in greater detail in Part 5. All you need to know for now is Th17 is the loose cannon cop who shoots first, asks questions later.41-43

THE RED HERRING

This is the definition of an autoimmune disease. It is a condition where the immune system identifies self-antigens as foreign and attacks its own body.44 In other words, the police accidently shoot the residents.

One popular theory of how autoimmune disease comes about is the viral mimicry theory. A virus enters the body that mimics self-antigens.14 In the process of fighting the virus, the immune system ends up identifying the mimicked self-antigens as foreign.6, 7, 45

For this to happen, the body has to be in an inflamed state. That way APCs provide the co-stimulation required and they also suppress Treg cells which would otherwise prevent a reaction to self. This is why the theorists looked at viruses. Not only would they mimic self-antigens, they’d also create the necessary inflammation.7, 45

However, we’ve just seen that wheat does an equally good job of providing the co-stimulation and shutting down Treg’s. And wheat may provide the mimicry as well, so forget the virus.20, 44, 46-48

Of the over 100 autoimmune conditions identified, the trigger has been discovered for only a handful. One of those is celiac disease. In this condition, gliadin from wheat binds a protein in the body called tissue transglutaminase (tTG). The immune system reacts to tTG-gliadin antigens causing it to attack the digestive tract.39, 49, 50

Gliadin may also cross-react with neural components of the brain and contribute to conditions like multiple sclerosis, gluten ataxia, and autism.46, 47, 51 Similarly, WGA is able to bind to many different cells once inside the body.20, 26, 31 While responding to WGA, the immune system will sometimes also react to its binding tissues.20, 52

What all of this amounts to is the ending to that home invasion story none of us want to hear. Wheat and the police end up in a tense standoff and guns are drawn. Tragically your son gets mistaken for one of the invaders and gets killed in the cross-fire.

Fortunately, while wheat can dysregulate the immune system in all of us, not everyone who eats it develops an autoimmune disease. In the final part of this series we’ll talk about how genetic susceptibility is required for disease.

Read The Wheat Series Part 5: Pulling the Trigger on a Loaded Chamber HERE

 

REFERENCES

[1]du Pre, M.F. and J.N. Samsom, Adaptive T-cell responses regulating oral tolerance to protein antigen. Allergy, 2011. 66(4): p. 478-90.

[2]McFall-Ngai, M., Adaptive immunity: care for the community. Nature, 2007. 445(7124): p. 153.

[3]Ohnmacht, C., et al., Intestinal microbiota, evolution of the immune system and the bad reputation of pro-inflammatory immunity. Cell Microbiol, 2011. 13(5): p. 653-9.

[4]Murphy, K., et al., Janeway’s immunobiology. 8th ed. 2012, New York: Garland Science. xix, 868 p.

[5]Lenschow, D.J., T.L. Walunas, and J.A. Bluestone, CD28/B7 system of T cell costimulation. Annu Rev Immunol, 1996. 14: p. 233-58.

[6]Oldstone, M.B.A., Molecular mimicry and immune-mediated diseases. Faseb Journal, 1998. 12(13): p. 1255-1265.

[7]Wucherpfennig, K.W. and J.L. Strominger, MOLECULAR MIMICRY IN T-CELL-MEDIATED AUTOIMMUNITY – VIRAL PEPTIDES ACTIVATE HUMAN T-CELL CLONES SPECIFIC FOR MYELIN BASIC-PROTEIN. Cell, 1995. 80(5): p. 695-705.

[8]Smith, P.D., et al.,Intestinal macrophages and response to microbial encroachment. Mucosal Immunol, 2011. 4 (1): p. 31-42.

[9]Ahmed, T., et al., Immune response to food antigens: kinetics of food-specific antibodies in the normal population. Acta Paediatr Jpn, 1997. 39(3): p. 322-8.

[10]Seibold, F., Food-induced immune responses as origin of bowel disease? Digestion, 2005. 71(4): p. 251-260.

[11]Ganeshan, K., et al., Impairing oral tolerance promotes allergy and anaphylaxis: A new murine food allergy model. Journal of Allergy and Clinical Immunology, 2009. 123(1): p. 231-238.

[12]Williamson, E., G.M. Westrich, and J.L. Viney, Modulating dendritic cells to optimize mucosal immunization protocols. J Immunol, 1999. 163(7): p. 3668-75.

[13]de Aizpurua, H.J. and G.J. Russell-Jones, Oral vaccination. Identification of classes of proteins that provoke an immune response upon oral feeding. J Exp Med, 1988. 167(2): p. 440-51.

[14]Stepniak, D. and F. Koning, Celiac disease–sandwiched between innate and adaptive immunity. Hum Immunol, 2006. 67(6): p. 460-8.

[15]Scalapino, K.J. and D.I. Daikh, CTLA-4: a key regulatory point in the control of autoimmune disease. Immunol Rev, 2008. 223: p. 143-55.

[16]Battaglia, M., et al., IL-10-producing T regulatory type 1 cells and oral tolerance. Ann N Y Acad Sci, 2004. 1029: p. 142-53.

[17]Wing, K. and S. Sakaguchi, Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol, 2010. 11(1): p. 7-13.

[18]Veldman, C., A. Nagel, and M. Hertl, Type I regulatory T cells in autoimmunity and inflammatory diseases. International Archives of Allergy and Immunology, 2006. 140(2): p. 174-183.

[19]Macdonald, T.T. and G. Monteleone, Immunity, inflammation, and allergy in the gut. Science, 2005. 307(5717): p. 1920-5.

[20]Vojdani, A., Lectins, agglutinins, and their roles in autoimmune reactivities. Altern Ther Health Med, 2015. 21 Suppl 1: p. 46-51.

[21]Drago, S., et al., Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol, 2006. 41(4): p. 408-19.

[22]Fasano, A., Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation Living Life on the Edge of the Wall. American Journal of Pathology, 2008. 173(5): p. 1243-1252.

[23]Fasano, A., Surprises from celiac disease. Sci Am, 2009. 301(2): p. 54-61.

[24]Lammers, K.M., et al., Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology, 2008. 135(1): p. 194-204 e3.

[25]Lavelle, E.C., et al., Mucosal immunogenicity of plant lectins in mice. Immunology, 2000. 99(1): p. 30-7.

[26]Pusztai, A., et al., Antinutritive effects of wheat-germ agglutinin and other N-acetylglucosamine-specific lectins. Br J Nutr, 1993. 70(1): p. 313-21.

[27]Ertl, B., et al., Lectin-mediated bioadhesion: preparation, stability and caco-2 binding of wheat germ agglutinin-functionalized Poly(D,L-lactic-co-glycolic acid)-microspheres. J Drug Target, 2000. 8(3): p. 173-84.

[28]Gabor, F., M. Stangl, and M. Wirth, Lectin-mediated bioadhesion: binding characteristics of plant lectins on the enterocyte-like cell lines Caco-2, HT-29 and HCT-8. J Control Release, 1998. 55(2-3): p. 131-42.

[29]Antvorskov, J.C., et al., Dietary gluten alters the balance of pro-inflammatory and anti-inflammatory cytokines in T cells of BALB/c mice. Immunology, 2013. 138(1): p. 23-33.

[30]Bernardo, D., et al., Is gliadin really safe for non-coeliac individuals? Production of interleukin 15 in biopsy culture from non-coeliac individuals challenged with gliadin peptides. Gut, 2007. 56(6): p. 889-890.

[31]Dalla Pellegrina, C., et al., Effects of wheat germ agglutinin on human gastrointestinal epithelium: insights from an experimental model of immune/epithelial cell interaction. Toxicol Appl Pharmacol, 2009. 237(2): p. 146-53.

[32]Jelinkova, L., et al., Gliadin stimulates human monocytes to production of IL-8 and TNF-alpha through a mechanism involving NF-kappaB. FEBS Lett, 2004. 571(1-3): p. 81-5.

[33]Junker, Y., et al., Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med, 2012. 209(13): p. 2395-408.

[34]Palova-Jelinkova, L., et al., Gliadin fragments induce phenotypic and functional maturation of human dendritic cells. J Immunol, 2005. 175(10): p. 7038-45.

[35]Nikulina, M., et al., Wheat gluten causes dendritic cell maturation and chemokine secretion. J Immunol, 2004. 173(3): p. 1925-33.

[36]Harris, K.M., A. Fasano, and D.L. Mann, Monocytes differentiated with IL-15 support Th17 and Th1 responses to wheat gliadin: implications for celiac disease. Clin Immunol, 2010. 135(3): p. 430-9.

[37]Palova-Jelinkova, L., et al., Pepsin digest of wheat gliadin fraction increases production of IL-1beta via TLR4/MyD88/TRIF/MAPK/NF-kappaB signaling pathway and an NLRP3 inflammasome activation. PLoS One, 2013. 8(4): p. e62426.

[38]Thomas, K.E., et al., Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease. J Immunol, 2006. 176(4): p. 2512-21.

[39]Tuckova, L., et al., Activation of macrophages by gliadin fragments: isolation and characterization of active peptide. J Leukoc Biol, 2002. 71(4): p. 625-31.

[40]Ejsing-Duun, M., et al., Dietary gluten reduces the number of intestinal regulatory T cells in mice. Scandinavian Journal of Immunology, 2008. 67(6): p. 553-559.

[41]Langrish, C.L., et al., IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med, 2005. 201(2): p. 233-40.

[42]Evans, H.G., et al., In vivo activated monocytes from the site of inflammation in humans specifically promote Th17 responses. Proc Natl Acad Sci U S A, 2009. 106(15): p. 6232-7.

[43]Mesquita Jr, D., et al., Autoimmune diseases in the TH17 era. Braz J Med Biol Res, 2009. 42(6): p. 476-86.

[44]Sollid, L.M. and B. Jabri, Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat Rev Immunol, 2013. 13(4): p. 294-302.

[45]Oldstone, M.B.A., MOLECULAR MIMICRY AND AUTOIMMUNE-DISEASE. Cell, 1987. 50(6): p. 819-820.

[46]Hadjivassiliou, M., et al., Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia. Neurology, 2006. 66(3): p. 373-7.

[47]Vojdani, A., et al., Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutr Neurosci, 2004. 7(3): p. 151-61.

[48]Alaedini, A., et al., Immune cross-reactivity in celiac disease: anti-gliadin antibodies bind to neuronal synapsin I. J Immunol, 2007. 178(10): p. 6590-5.

[49]Dieterich, W., et al., Identification of tissue transglutaminase as the autoantigen of celiac disease. Nature Medicine, 1997. 3(7): p. 797-801.

[50]Molberg, O., et al., Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nature Medicine, 1998. 4(6): p. 713-717.

[51]Vojdani, A., D. Kharrazian, and P.S. Mukherjee, The prevalence of antibodies against wheat and milk proteins in blood donors and their contribution to neuroimmune reactivities. Nutrients, 2014. 6(1): p. 15-36.

[52]Falth-Magnusson, K. and K.E. Magnusson, Elevated levels of serum antibodies to the lectin wheat germ agglutinin in celiac children lend support to the gluten-lectin theory of celiac disease. Pediatr Allergy Immunol, 1995. 6(2): p. 98-102.

The Wheat Series Part 3: Setting Off the Bacterial Alarm Bells – With or Without the Bacteria | The Paleo Diet

Did you miss The Wheat Series Part 1: Wheat and the Immune System? Read it HERE.
Did you miss The Wheat Series Part 2: Opening the Barrier to Poor Gut Health? Read it HERE.

It’s a battle that’s been waging for millions of years. Viruses, bacteria, and a variety of pathogens looking for a nice warm home have evolved more and more sophisticated techniques to evade our immune systems. In response, our immune systems developed an array of specialized cells to launch remarkably targeted attacks at these unwanted invaders.

In the face of this cellular army, pathogens discovered one of their best weapons is a microscopic form of hide-and-seek.

Viruses mimic our bodies so immune cells pass them by.1, 2 Meningitis hangs out in the nervous system where immune cells dare not go, and HIV takes up home in immune cells themselves – after, of course, dismantling a few defenses.

These are all ways of telling the immune system “keep moving, nothing to see here.”

But what would happen if instead of looking for a good hiding place, an invader actually tried to set off the immune system alarm bells? More importantly, why would an invader want to do that?

Well, imagine you’re a plant. When some hungry animal looks at you and says “lunch” you can’t really run away. Nor can you fight back. So what do you do?

You make sure that after the animal has its meal, it is sick enough to think twice about ever touching one of your brethren.

Enter wheat.

In Part One of this series on wheat, I talked about how the normally sluggish digestive immune system can become inappropriately inflamed and lead to disease. Three things can cause this: intestinal permeability (leaky gut); chronic or too high a bacterial load; and dietary antigens.

Wheat has the unique distinction of influencing all three.

The first, intestinal permeability, is promoted by wheat through the release of zonulin.3-5 We covered that in Part Two.

Let’s get to Part Three – chronic or too high a bacterial load.

Of course, you’ve probably already realized that wheat is not bacteria. True. But the same way viruses mimic our bodies, wheat has evolved ways to “mimic” bacteria. All with the purpose of setting off the immune system alarm bells – whether the bacteria is there or not.

BACTERIAL ALARM BELLS

Our bodies actually like bacteria.

At least when they stay where they belong – in the gut.6-9 In fact, in Part One, we talked about how much of our digestive immune system evolved to allow us to live with this bacteria.7, 9-11

It’s when the bacteria – especially the less friendly types such as gram negative bacteria – get into our bodies that the immune system takes action. As a result, our immune cells have developed critical tools for the sole purpose of hunting down and identifying bacteria inside the body.

Fortunately, the bad gram negative bacteria has a tell. All over its surface is something called lipopolysaccharide (LPS).12

Antigen presenting cells (APCs) hunt down bacteria using two receptors for LPS called TLR-4 and CD14.12, 13 When LPS binds TLR-4 and CD14, the immune system alarm bells go off.

The diagram below shows the basics of this sophisticated alarm system,14 but the end result is simple. The immune system spins up and inflammation ensues.

The Wheat Series Part 3: Setting Off the Bacterial Alarm Bells – With or Without the Bacteria | The Paleo Diet

WHEAT – THE GREAT BACTERIAL MIMICKER

That subtitle is actually only partially accurate. A better description might be “wheat – the boy who cried bacterial wolf.”

The problem is our bodies never learn to ignore this particular boy.

Wheat has developed a variety of sophisticated techniques for activating the LPS response. But in some cases, it does it differently from LPS, bypassing key regulatory steps such as CD14 which would otherwise prevent inflammation in places we don’t want it.6, 10

A full description of these mechanisms is beyond the scope of this article and probably your boredom limit. So, the following is only a cursory description, but with lots of journal references that will keep the geekiest of you happy.

MECHANISM 1: LET BACTERIA IN

Part Two gives an in depth description of how wheat opens up the digestive tract barrier and allows things in our gut to get into our bodies. This includes our intestinal bacteria.15

The Wheat Series Part 3: Setting Off the Bacterial Alarm Bells – With or Without the Bacteria | The Paleo Diet

In other words, wheat actually lets the wolf into the chicken coop and then cries wolf.

MECHANISM 2: HOMEBREW LPS

Wheat contains its own LPS-like molecule, sometimes called LPSw, that has similar effects but admittedly isn’t as potent as the real thing.16, 17 In one study on mice, LPSw was able to promote a bacterial immune response.17

MECHANISM 3: ATI’S

(No It’s Not a Computer Company)

At the barrier of our gut are a special type of immune cell called dendritic cells. Constantly sampling the contents of our digestive tract, tthey are the on/off switch of the immune system.18 Think of them as Paul Revere riding back to the immune system yelling “the bacteria are coming!”

Wheat contains molecules that very potently activates dendritic cells called α-Amylase/Trypsin Inhibitors (ATIs).19 They act through TLR-4 on the dendrites. And sorry to those of you who love to say you’re “gluten-free” – ATIs, which exist in many grains, are found in a different part than gluten.

ATI’s are responsible for a long known condition called Baker’s Asthma named so because it was common among people who worked with flour.20

MECHANISM 4: SKIP THE ALARM BUT GET THE RESPONSE

TLR-4 and CD14 are not strongly expressed in the gut immune system making it hard to sound the bacterial alarm in the gut.21-23 In an area of the body that’s exposed to bacteria thousands of times each day, an inflammatory response isn’t something we want.21, 22

So it should be concerning to hear that wheat has developed ways of causing the inflammatory response without bothering with TLR-4 or CD14.

The ways wheat does it gets complex. We’ll just touch on them.

First, in several studies, small amounts of gluten were able to flip the dendritic cell’s “on switch” in mice and start an inflammatory response without touching TLR-4.24, 25

Another molecule in wheat (there’s a lot) called wheat germ agglutinin (WGA) can bind and pass right through the gut barrier to interact with immune cells on the other side. WGA then promotes a highly inflammatory response26, 27 including turning dendritic cells on.

Finally, remember all those antigen presenting cells in the gut that avoid sounding the bacterial alarm bells by simply not expressing CD14? Gliadin promotes something called IL-15 which is highly effective at activating APCs that don’t express CD14.28-33

And of a variety of foods tested, gliadin was the only one able to so effectively activate these cells.33

WHAT HAPPENS WHEN YOU PREPARE FOR AN INVASION WITHOUT THE INVASION?

That’s a lot of science and frankly we only just skimmed the surface. So here’s the point – wheat is amazingly effective at activating the bacterial defence mechanisms of our immune cells.

More importantly, this response happens in everyone and not just celiac disease (though there’s evidence it’s more pronounced in celiacs).29

So what happens when our bodies mount a defense against bacteria that isn’t there? The answer to that question is the focus of the final part to this series. But the short answer is it creates a constant state of inflammation as long as we continue to eat wheat.34, 35

Recent research is now associating a state of constant inflammation with the onset of nearly all major chronic diseases36 including heart disease,37 Alzheimer’s disease,38 diabetes,39 cancer,40, 41 and overall morbidity.42

But the question remains does the inflammation that results from wheat inappropriately setting off the bacterial alarms also contribute to these conditions?

That’s a question we’ll hope to delve into in the next two parts. But fortunately, by eating a wheat-free Paleo diet, it’s a question you may never have to worry about.

Read The Wheat Series Part 4: Home Invasion HERE

 

REFERENCES

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[2]Amara, A. and J. Mercer, Viral apoptotic mimicry. Nat Rev Microbiol, 2015.

[3]Lammers, K.M., et al., Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology, 2008. 135(1): p. 194-204 e3.

[4]Drago, S., et al., Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol, 2006. 41(4): p. 408-19.

[5]Visser, J., et al., Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms. Ann N Y Acad Sci, 2009. 1165: p. 195-205.

[6]Ohnmacht, C., et al., Intestinal microbiota, evolution of the immune system and the bad reputation of pro-inflammatory immunity. Cell Microbiol, 2011. 13(5): p. 653-9.

[7]McFall-Ngai, M., Adaptive immunity: care for the community. Nature, 2007. 445(7124): p. 153.

[8]Ivanov, II, et al., Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell, 2009. 139(3): p. 485-98.

[9]Cao, A.T., et al., Th17 cells upregulate polymeric Ig receptor and intestinal IgA and contribute to intestinal homeostasis. J Immunol, 2012. 189(9): p. 4666-73.

[10]Smith, P.D., et al., Intestinal macrophages and response to microbial encroachment. Mucosal Immunol, 2011. 4(1): p. 31-42.

[11]Arrieta, M.-C. and B.B. Finlay, The commensal microbiota drives immune homeostasis. Frontiers in Immunology, 2012. 3.

[12]Kawai, T., et al., Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol, 2001. 167(10): p. 5887-94.

[13]Perera, P.Y., et al., CD11b/CD18 acts in concert with CD14 and Toll-like receptor (TLR) 4 to elicit full lipopolysaccharide and taxol-inducible gene expression. J Immunol, 2001. 166(1): p. 574-81.

[14]Buer, J. and R. Balling, Mice, microbes and models of infection. Nat Rev Genet, 2003. 4(3): p. 195-205.

[15]Fasano, A., Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev, 2011. 91(1): p. 151-75.

[16]Yamazaki, K., J.A. Murray, and H. Kita, Innate immunomodulatory effects of cereal grains through induction of IL-10. Journal of Allergy and Clinical Immunology, 2008. 121(1): p. 172-178.

[17]Nishizawa, T., et al., Homeostasis as regulated by activated macrophage. I. Lipopolysaccharide (LPS) from wheat flour: isolation, purification and some biological activities. Chem Pharm Bull (Tokyo), 1992. 40(2): p. 479-83.

[18]Williamson, E., G.M. Westrich, and J.L. Viney, Modulating dendritic cells to optimize mucosal immunization protocols. J Immunol, 1999. 163(7): p. 3668-75.

[19]Junker, Y., et al., Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med, 2012. 209(13): p. 2395-408.

[20]Sapone, A., et al., Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med, 2012. 10: p. 13.

[21]Kamada, N., et al., Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Invest, 2008. 118(6): p. 2269-80.

[22]Nagler-Anderson, C., Tolerance and immunity in the intestinal immune system. Critical Reviews in Immunology, 2000. 20(2): p. 103-120.

[23]Smythies, L.E., et al., Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J Clin Invest, 2005. 115(1): p. 66-75.

[24]Palova-Jelinkova, L., et al., Gliadin fragments induce phenotypic and functional maturation of human dendritic cells. J Immunol, 2005. 175(10): p. 7038-45.

[25]Nikulina, M., et al., Wheat gluten causes dendritic cell maturation and chemokine secretion. J Immunol, 2004. 173(3): p. 1925-33.

[26]Dalla Pellegrina, C., et al., Effects of wheat germ agglutinin on human gastrointestinal epithelium: insights from an experimental model of immune/epithelial cell interaction. Toxicol Appl Pharmacol, 2009. 237(2): p. 146-53.

[27]Gabor, F., M. Stangl, and M. Wirth, Lectin-mediated bioadhesion: binding characteristics of plant lectins on the enterocyte-like cell lines Caco-2, HT-29 and HCT-8. J Control Release, 1998. 55(2-3): p. 131-42.

[28]Harris, K.M., A. Fasano, and D.L. Mann, Monocytes differentiated with IL-15 support Th17 and Th1 responses to wheat gliadin: implications for celiac disease. Clin Immunol, 2010. 135(3): p. 430-9.

[29]Bernardo, D., et al., Is gliadin really safe for non-coeliac individuals? Production of interleukin 15 in biopsy culture from non-coeliac individuals challenged with gliadin peptides. Gut, 2007. 56(6): p. 889-890.

[30]Jelinkova, L., et al., Gliadin stimulates human monocytes to production of IL-8 and TNF-alpha through a mechanism involving NF-kappaB. FEBS Lett, 2004. 571(1-3): p. 81-5.

[31]Palova-Jelinkova, L., et al., Pepsin digest of wheat gliadin fraction increases production of IL-1beta via TLR4/MyD88/TRIF/MAPK/NF-kappaB signaling pathway and an NLRP3 inflammasome activation. PLoS One, 2013. 8(4): p. e62426.

[32]Thomas, K.E., et al., Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease. J Immunol, 2006. 176(4): p. 2512-21.

[33]Tuckova, L., et al., Activation of macrophages by gliadin fragments: isolation and characterization of active peptide. J Leukoc Biol, 2002. 71(4): p. 625-31.

[34]Nilsen, E.M., et al., Gluten activation of peripheral blood T cells induces a Th0-like cytokine pattern in both coeliac patients and controls. Clin Exp Immunol, 1996. 103(2): p. 295-303.

[35]Antvorskov, J.C., et al., Dietary gluten alters the balance of pro-inflammatory and anti-inflammatory cytokines in T cells of BALB/c mice. Immunology, 2013. 138(1): p. 23-33.

[36]Hotamisligil, G.S., Inflammation and metabolic disorders. Nature, 2006. 444(7121): p. 860-867.

[37]Libby, P., P.M. Ridker, and A. Maseri, Inflammation and atherosclerosis. Circulation, 2002. 105(9): p. 1135-1143.

[38]Akiyama, H., et al., Inflammation and Alzheimer’s disease. Neurobiology of Aging, 2000. 21(3): p. 383-421.

[39]Xu, H.Y., et al., Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. Journal of Clinical Investigation, 2003. 112(12): p. 1821-1830.

[40]Grivennikov, S.I., F.R. Greten, and M. Karin, Immunity, Inflammation, and Cancer. Cell, 2010. 140(6): p. 883-899.

[41]Coussens, L.M. and Z. Werb, Inflammation and cancer. Nature, 2002. 420(6917): p. 860-867.

[42]Krabbe, K.S., M. Pedersen, and H. Bruunsgaard, Inflammatory mediators in the elderly. Exp Gerontol, 2004. 39(5): p. 687-99.

The Wheat Series Part 1: Wheat and the Immune System | The Paleo Diet

With a rapidly growing body of nutrition science covering everything from dietary proteins, to microflora composition, to caloric expenditure and cell bioenergetics, it’s surprising that still one of the hardest arguments to counter remains “I’ve always eaten it and I’m fine.” It’s a point my 97 year old grandmother likes to make every time she asks me about my research.

Let me tell you, arguing with a 97 year old about health is not easy.

The epidemiological version of the “I’m fine” argument is an assertion we hear a lot: while evidence exists that people with celiac disease cannot eat wheat, there is no proof that consuming a gluten-free diet will benefit the rest of the population.1, 2

Celiac sufferers can’t eat wheat. We know that. But it certainly appears that most people can have their bagel, get on with their days, and be just fine. Even live to see a century.

The “I’m fine” argument certainly appears to hold up on the surface. The underlying danger, however, is that the term “fine” is so remarkably subjective.

Take the case of tennis player Novak Djokovic. He went gluten-free in 2011 and then proceeded to have the most successful season in tennis history reaching number one in the process. He was certainly fine when he was eating wheat. He was just better without it.

So let’s take the subjectivity out of fine. Since we define a Paleo Diet as eating what we were designed to eat, perhaps a Paleo way of defining “fine” is functioning the way we were designed to function.

Looked at this way, there is in fact a great deal of research showing the various ways in which wheat causes our bodies to function abnormally. A select unfortunate few, such as celiacs and diabetics, may take the brunt of it, but none of us function normally eating wheat. None of us are fine.

This article is the first part in our wheat series summarizing current research on wheat and the immune system. The next few pieces will detail how wheat causes our bodies to stop functioning the way they were designed to function and can, ultimately, lead to disease. But to understand the damage, let’s start by examining what our digestive immune system looks like when it’s functioning just fine.

The Fine-Functioning Gut

Our digestive immune system is one of the most complex and robust systems in our bodies. Some 50×109 immune cells reside in the gut-associated lymphoid tissue (GALT) which makes up the bulk of our immune cells.3

But why are there so many immune cells in the gut? Because, as the image below shows, the gut is an area of constant stress. The digestive tract is continually bombarded by bacteria, food particles, and pathogens.4,5

The Wheat Series Part 1: I’ve Always Eaten It and I’m Fine… Right? | The Paleo Diet

MacDonald, T.T. and G. Monteleone, Immunity, inflammation, and allergy in the gut. Science, 2005. 307(5717): p. 1920-1925.

This image is actually a highly simplified version of what goes on in the GALT. The reality is a complex mix of T Cells, monocytes, cytokines, chemokines, interleukins, adhesion molecules, and intricate processes that would have you running for a book on brain surgery to give yourself some light reading.

Don’t worry, we’re not going to cover all that.

We’re just going to focus on a few key concepts that will hopefully prove to be fascinating. But to do that we need to introduce just a few of the important players in the gut:

First is a row of tightly packed cells that keep the contents of the digestive tract from getting into the body. It is our first line of defense and normally very effective at keeping things out.6,7Leaky gut” is just a term we use for when this barrier breaks down.

Next in our line of defense are antigen presenting cells (APCs.) They are the macrophages, dendritic, and plasma cells in the image above. These cells “sample” all the food particles, bacteria, and pathogens in the gut and present them to the immune system.

The final players you need to know for this article are T Cells. They are the generals of the immune system. Antigens are presented to the T Cells and then they decide how to respond.

It’s All About Bacteria

Generally when we think about what our immune system deals with, we think about viruses and pathogens and all those nasty things on airplanes and in our kid’s kindergarten classes.

But the truth is, dealing with a pathogen is a rare thing for our digestive immune system. Most of its energy is spent managing our microflora – those beneficial bacteria we pop probiotics and eat yoghurt to encourage. We need them for our health. We just also need them to stay in our gut because they aren’t so beneficial inside our bodies.8,9,10,11

If you’re wondering how big a role these bacteria play, remember there are more cells in our microflora than cells in our own bodies.

They are so important in fact that several researchers proposed that our digestive immune system evolved not because of pathogens but to allow us to live in harmony with our microflora.5,9,11,12

This is a critical distinction!

If a pathogen or even the normally healthy bacteria in our gut gets into our blood, our bodies mount an immediate and strong inflammatory response.13,14 This inflammation is what causes the aches, fever, and chill we associated with being sick.

The response to a bacterial infection in circulation, though damaging, is necessary and keeps us alive. Fortunately, bacteria rarely gets into our blood.

In the gut, on the other hand, the immune system is exposed to bacteria thousands of times each day. An inflammatory response every time would be deadly.5, 15 There’s even a name for this out of control inflammation – sepsis.16

As a result, the digestive immune system takes a very different tact with our beneficial bacteria. It becomes anergic – meaning it actually blocks inflammation.17,18 Special immune cells in the gut called T regulatory (Treg) cells and a unique type of APC cell actively shut down the inflammatory response and then quietly take out the invading bacteria one-by-one.3,15

The Wheat Series Part 1: I’ve Always Eaten It and I’m Fine… Right? | The Paleo Diet

Zeng, H. and H. Chi, Metabolic control of regulatory T cell development and function. Trends in Immunology. 36(1): p. 3-12.

We All Get Inflamed Sometimes

As effective as this system is, bacteria still periodically get the upper hand and an inflammatory response in the gut becomes a necessary evil.

Several things happen. First, gut APCs lose their anergy.20, 21  Second, naturally inflammatory immune cells from the blood are recruited to the gut.5,22 Finally, the Treg cells that are so effective at keeping inflammation down give way to a unique T cell called Th17 cells.

Th17 cells are powerful immune cells believed to have a single purpose – control bacterial infections.8,11,23 They are highly effective at killing bacteria, but they can also be very damaging to our own bodies. It’s the price we pay to manage our microflora, but not one we want to pay often.9,10

Ultimately, the gut remains fine as long as the inflammation ramps up quickly, kills the infection, and then backs down.

The following diagram shows this shift in Treg/Th17 balance during infection:

The Wheat Series Part 1: I’ve Always Eaten It and I’m Fine… Right? | The Paleo Diet

Arrieta, M.-C. and B.B. Finlay, The commensal microbiota drives immune homeostasis. Frontiers in Immunology, 2012. 3

When It Stops Being Fine

Problems arise when the bacterial infestation becomes overwhelming or when the inflammation simply doesn’t go away.5,8

As the inflammation continues, the imbalance between anti-inflammatory Treg cells and inflammatory Th17 cells builds on itself until finally the Tregs can’t control the Th17 cells anymore.24,25,26,27

The Wheat Series Part 1: I’ve Always Eaten It and I’m Fine… Right? | The Paleo Diet

Ohnmacht, C., et al., Intestinal microbiota, evolution of the immune system and the bad reputation of pro-inflammatory immunity. Cell Microbiol, 2011. 13(5): p. 653-9.

No longer protective, Th17 cells can then enter other parts of the bodies and contribute to a variety of chronic diseases.28,29 such as asthma,30 heart disease,31, 32 and most autoimmune conditions28,33 including celiac disease,34,35 type I diabetes,36,37 Crohn’s disease,38,39 rheumatoid arthritis,29,40 and multiple sclerosis.41

The Three Pathways to a Not Fine Gut

This highly pathogenic Th17 imbalance is a result of an abnormally functioning digestive immune system. Three things are known to cause it:

  1. Increased intestinal permeability (leaky gut)
  2. Chronic or two high a bacterial load
  3. Food particles that can hurt immune function

So now that you’ve plowed through all of that only-interesting-to-people-like-me immune function information, here’s the really fascinating point:

Wheat is the only food we’re aware of that causes all three.

In the remaining articles in this series, I will share with you the surprisingly large number of ways in which wheat breaks down the normal intestinal immune system and leads to damaging Th17 development.42, 43

More importantly, I will show you that it happens in everyone. In other words, a normally healthy gut exposed to wheat isn’t fine in anyone. Stay tuned!

Read The Wheat Series Part 2: Opening the Barrier to Poor Gut Health HERE

Trevor Connor

Trevor Connor | The Paleo DietTrevor Connor is Dr. Cordain’s last mentored graduate student and will complete his M.S. in HES and Nutrition from the Colorado State University this year and later enter the Ph.D. program. Connor was the Principle Investigator in a large case study, approximately 100 subjects, in which he and Dr. Cordain examined autoimmune patients following The Paleo Diet or Paleo-like diets.

 

REFERENCES

[1]Ferch, C.C. and W.D. Chey, Irritable Bowel Syndrome and Gluten Sensitivity Without Celiac Disease: Separating the Wheat From the Chaff. Gastroenterology, 2012. 142(3): p. 664-666.

[2]Gaesser, G.A. and S.S. Angadi, Gluten-Free Diet: Imprudent Dietary Advice for the General Population? Journal of the Academy of Nutrition and Dietetics, 2012. 112(9): p. 1330-1333.

[3]du Pre, M.F. and J.N. Samsom, Adaptive T-cell responses regulating oral tolerance to protein antigen. Allergy, 2011. 66(4): p. 478-90.
[4]MacDonald, T.T. and G. Monteleone, Immunity, inflammation, and allergy in the gut. Science, 2005. 307(5717): p. 1920-1925.

[5]Smith, P.D., et al., Intestinal macrophages and response to microbial encroachment. Mucosal Immunol, 2011. 4(1): p. 31-42.

[6]Visser, J., et al., Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms. Ann N Y Acad Sci, 2009. 1165: p. 195-205.

[7]Yu, Q.H. and Q. Yang, Diversity of tight junctions (TJs) between gastrointestinal epithelial cells and their function in maintaining the mucosal barrier. Cell Biol Int, 2009. 33(1): p. 78-82.

[8]Ohnmacht, C., et al., Intestinal microbiota, evolution of the immune system and the bad reputation of pro-inflammatory immunity. Cell Microbiol, 2011. 13(5): p. 653-9.

[9]McFall-Ngai, M., Adaptive immunity: care for the community. Nature, 2007. 445(7124): p. 153.

[10]Ivanov, II, et al., Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell, 2009. 139(3): p. 485-98.

[11]Cao, A.T., et al., Th17 cells upregulate polymeric Ig receptor and intestinal IgA and contribute to intestinal homeostasis. J Immunol, 2012. 189(9): p. 4666-73.

[12]Arrieta, M.-C. and B.B. Finlay, The commensal microbiota drives immune homeostasis. Frontiers in Immunology, 2012. 3.

[13]Koj, A., Initiation of acute phase response and synthesis of cytokines. Biochim Biophys Acta, 1996. 1317(2): p. 84-94.

[14]Ohl, M.E. and S.I. Miller, Salmonella: a model for bacterial pathogenesis. Annu Rev Med, 2001. 52: p. 259-74.

[15]Smythies, L.E., et al., Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J Clin Invest, 2005. 115(1): p. 66-75.

[16]Bone, R.C., et al., DEfinitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. the accp/sccm consensus conference committee. american college of chest physicians/society of critical care medicine. Chest, 1992. 101(6): p. 1644-1655.

[17]Kamada, N., et al., Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Invest, 2008. 118(6): p. 2269-80.

[18]Nagler-Anderson, C., Tolerance and immunity in the intestinal immune system. Critical Reviews in Immunology, 2000. 20(2): p. 103-120.

[19]Zeng, H. and H. Chi, Metabolic control of regulatory T cell development and function. Trends in Immunology. 36(1): p. 3-12.

[20]Williamson, E., G.M. Westrich, and J.L. Viney, Modulating dendritic cells to optimize mucosal immunization protocols. J Immunol, 1999. 163(7): p. 3668-75.

[21]Burcelin, R., L. Garidou, and C. Pomie, Immuno-microbiota cross and talk: the new paradigm of metabolic diseases. Semin Immunol, 2012. 24(1): p. 67-74.

[22]Yamazaki, K., J.A. Murray, and H. Kita, Innate immunomodulatory effects of cereal grains through induction of IL-10. J Allergy Clin Immunol, 2008. 121(1): p. 172-178 e3.

[23]Reynolds, J.M., et al., Cutting edge: regulation of intestinal inflammation and barrier function by IL-17C. J Immunol, 2012. 189(9): p. 4226-30.

[24]Zhou, X., et al., Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol, 2009. 10(9): p. 1000-7.

[25]Scalapino, K.J. and D.I. Daikh, CTLA-4: a key regulatory point in the control of autoimmune disease. Immunol Rev, 2008. 223: p. 143-55.

[26]Ejsing-Duun, M., et al., Dietary gluten reduces the number of intestinal regulatory T cells in mice. Scand J Immunol, 2008. 67(6): p. 553-9.

[27]Lochner, M., et al., In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORgamma t+ T cells. J Exp Med, 2008. 205(6): p. 1381-93.

[28]Kamada, N., et al., Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol, 2013. 13(5): p. 321-35.

[29]Tesmer, L.A., et al., Th17 cells in human disease. Immunological Reviews, 2008. 223: p. 87-113.

[30]Cosmi, L., et al., Th17 cells: new players in asthma pathogenesis. Allergy, 2011. 66(8): p. 989-98.

[31]Taleb, S., A. Tedgui, and Z. Mallat, IL-17 and Th17 cells in atherosclerosis: subtle and contextual roles. Arterioscler Thromb Vasc Biol, 2015. 35(2): p. 258-64.

[32]van Bruggen, N. and W. Ouyang, Th17 cells at the crossroads of autoimmunity, inflammation, and atherosclerosis. Immunity, 2014. 40(1): p. 10-2.

[33]Singh, R.P., et al., Th17 cells in inflammation and autoimmunity. Autoimmun Rev, 2014. 13(12): p. 1174-81.

[34]Monteleone, I., et al., Characterization of IL-17A-producing cells in celiac disease mucosa. J Immunol, 2010. 184(4): p. 2211-8.

[35]Castellanos-Rubio, A., et al., TH17 (and TH1) signatures of intestinal biopsies of CD patients in response to gliadin. Autoimmunity, 2009. 42(1): p. 69-73.

[36]Kumar, P. and G. Subramaniyam, Molecular underpinnings of Th17 immune-regulation and their implications in autoimmune diabetes. Cytokine, 2015. 71(2): p. 366-76.

[37]Shao, S., et al., Th17 cells in type 1 diabetes. Cell Immunol, 2012. 280(1): p. 16-21.

[38]Elson, C.O., et al., Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology, 2007. 132(7): p. 2359-70.

[39]Brand, S., Crohn’s disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn’s disease. Gut, 2009. 58(8): p. 1152-67.

[40]Hirota, K., et al., Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med, 2007. 204(12): p. 2803-12.

[41]Du, C., et al., MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol, 2009. 10(12): p. 1252-9.

[42]Antvorskov, J.C., et al., Dietary gluten alters the balance of pro-inflammatory and anti-inflammatory cytokines in T cells of BALB/c mice. Immunology, 2013. 138(1): p. 23-33.

[43]Antvorskov, J.C., et al., Impact of dietary gluten on regulatory T cells and Th17 cells in BALB/c mice. PLoS One, 2012. 7(3): p. e33315.

Wheat: Opening the Barrier to Poor Gut Health | The Paleo Diet

Did you miss The Wheat Series Part 1: Wheat and the Immune System? Read it HERE.

It was a comment I’ve heard too many times. I was watching tennis with a friend who knew me as a cyclist, not as someone who researches nutrition. The commentators were discussing world No. 1 ranked tennis player Novak Djokovic’s newfound success since going on a gluten-free diet. My friend got noticeably irritated and finally blurted “I’m tired of this gluten-free fad! There’s not a scrap of evidence it makes a difference unless you have celiac disease.” As much as I wanted to, I chose not to respond, but thought to myself, “The bottom drawer of my research cabinet is awfully heavy for not having a scrap of anything in it.

This viewpoint that the health benefits of a gluten-free diet are more fad than science is a pervasive one. But what has led so many, including doctors and scientists, to say the research doesn’t exist?

Certainly the science is extensive for celiac disease where the role of gluten is indisputable. Gliadin, a protein in gluten, binds to a molecule in our bodies called tissue transglutaminase. In celiac patients it’s this new, combined molecule that sets off the inappropriate immune response.1, 2, 3

Without gluten, celiac disease couldn’t exist.

Recently other gluten-related disorders like gluten allergies and gluten ataxia have been identified.4, 5  But admittedly, these conditions affect only about 2% – 10% of the population. Outside of these diseases my friend has a point; research showing gluten having a direct pathogenic role, as it does in celiac disease, isn’t there.

But perhaps this is where the disconnect exists.

While a great deal of published research is showing that wheat and gluten can promote a large range of chronic conditions4, 6, 7, 8, gluten’s role is not so direct. Instead, gluten may breakdown the body’s natural defenses, setting up an inflammatory environment. This environment is highly conducive to a variety of chronic diseases in those of us who are unfortunate enough to have the wrong genetics.9, 10 Gluten sets the stage.

Looking at gluten this way, the bottom drawer of my cabinet suddenly gets a lot heavier. I hope to share a few posts on the ways in which wheat can set the stage for unwanted inflammation and disease. Let’s start with a surprising function that came out of celiac research.

LOOSENING OUR BORDERS

One of the most important roles of our gut, beside processing nutrients and hosting a rich microflora, is to provide a barrier blocking the entry of unwanted particles. Fortunately tight junctions (TJ) between the epithelial cells of our intestine carefully regulate entry of all but a few small molecules and essential nutrients.

Over the last 20 years, Dr. Alessio Fasano at the University of Maryland has researched breakdowns in this barrier, ultimately identifying a molecule produced in our guts called zonulin.14 Zonulin has the unique ability to dissolve the occludins, claudins, zonular occluden, and ZO-1 proteins that make up the structural cytoskeletons of our tight junctions.6, 15, 16, 17, 18

Put simply, zonulin can breakdown our barrier and increase intestinal permeability. An effect that’s often referred to around the web as “leaky gut.” It is rapid, reproducible, and fortunately, reversible.16

To date, two powerful triggers for zonulin have been identified.

The first trigger is exposure to bacteria in the intestine. Interestingly, infection by both pathogenic and “healthy” bacteria can have a triggering effect. However, it’s amplified with the “bad guys” as we can see from the chart below on the left.19

Wheat: Opening the Barrier to Poor Gut Health | The Paleo Diet
Wheat: Opening the Barrier to Poor Gut Health | The Paleo Diet
It is believed that zonulin evolved to protect us against bacterial colonization in the gut.6, 17, 19 When there’s an overload of bacteria in an otherwise healthy digestive tract, zonulin opens up the tight junctions allowing fluid to rush into the gut and flush out microorganisms.

The second powerful activator of the zonulin system is gliadin.

Gliadin fragments bind to the CXCR3 receptor on the epithelial cells of the gut. Then through a MyD88 signaling process, these epithelial cells release zonulin and cause an opening of tight junctions.6, 15, 17, 20, 21

It’s a complex process, but all you need to know is that gliadin can do this from inside the gut. It doesn’t have to get into our systems. More importantly, gluten is inappropriately high jacking a powerful defense mechanism designed to handle bacterial contamination.17

In the above right figure, we can see from Dr. Fasano’s research how gliadin’s ability to stimulate zonulin can be as powerful as bacterial triggers.6

Finally, while gliadin’s effect is much stronger in individuals with celiac disease, gliadin does not discriminate, and it happens in all peoples guts.6, 17

PERMEABLE CONSEQUENCES

With a healthy gut barrier, large molecules are degraded before entering the body and are well tolerated by the immune system.12 Intestinal permeability caused by gluten and bacteria allows these large molecules to get into circulation and act as antigens (activators) for the immune system.15, 17, 22

This becomes a real concern considering gluten is normally consumed with a meal. Its rapid effect on gut permeability happens at the same time that the gut is being hit by a large number of foreign antigens.

 

Wheat: Opening the Barrier to Poor Gut Health | The Paleo Diet

Dr. Fasano and his group proposed that once these antigens gain entry, they can be misinterpreted by the immune system in genetically susceptible individuals. The result is an inappropriate immune response that ultimately leads to chronic illness.6, 12, 15, 23, 24, 25In a healthy gut, these antigens would never gain access to the immune system.

The image above provides a nice representation of how gluten can open tight junctions and lead to diseases such as celiac disease and type 1 diabetes.6

LOSING THE BARRIER TO DISEASE

So, what does this all amount to? Intestinal permeability caused by either bacterial overgrowth or gluten (both of which are heavily influenced by diet) may be a key early step to set the body up for many chronic illness.

But is there any research? Fortunately, this is where I have to start using more drawers in my research cabinet.

Higher zonulin levels and intestinal permeability have been associated with and often precede many autoimmune conditions including type 1 diabetes,16, 30, 3132, 33celiac disease,17, 28, 34 multiple sclerosis,35, 36 rheumatoid arthritis,37, 38ankylosing spondylitis,37, 39 and Crohn’s disease.40, 41Eating wheat has been directly linked to diabetes.31, 42, 43, 44

A popular theory of autoimmune disease – called the molecular mimicry theory – proposed that autoimmune disease is initiated by viruses that mimic our bodies.26, 27 Dr. Fasano and his group suggested instead that dietary antigens passing through a leaky gut may be the environmental trigger. To test their theory, they were able to use a zonulin inhibitor to reduce the severity of celiac disease symptoms in humans 28 and the incidence of type 1 diabetes in mice.29

Intestinal permeability isn’t just associated with autoimmune conditions. Permeability may affect asthmatics by increasing their exposure to allergens.45, 46 Elevated zonulin levels have been found in irritable bowel disease 47, 48 and cancer.4950Even schizophrenia has recently been linked to gluten consumption and zonulin levels.51, 52

But a final question remains.

In a world where most people reach for a bagel and toast as soon as they get out of bed, intestinal permeability may just be a part of western life that gets an unfair rap by association. In other words, is it too easy to just link permeability with chronic disease? Does it really play a role?

In his 2011 review of zonulin and disease, Dr. Fasano addressed this question pointing out a number of studies where symptoms and incidence rates were reduced when gluten was removed from the diet or when zonulin’s effects were blocked.6

Wheat, a no-no for any good Paleo dieter, was clearly opening doors.

Read The Wheat Series Part 3: Setting Off the Bacterial Alarm Bells – With or Without the Bacteria HERE

REFERENCES

[1]Dieterich, W., et al., Identification of tissue transglutaminase as the autoantigen of celiac disease. Nature Medicine, 1997. 3(7): p. 797-801.

[2]Molberg, O., et al., Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nature Medicine, 1998. 4(6): p. 713-717.

[3]Plenge, R.M., Unlocking the pathogenesis of celiac disease. Nat Genet, 2010. 42(4): p. 281-2.

[4]Sapone, A., et al., Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med, 2012. 10: p. 13.

[5]Hadjivassiliou, M., et al., Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics. Brain, 2003. 126(Pt 3): p. 685-91.

[6]Fasano, A., Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev, 2011. 91(1): p. 151-75.

[7]Biesiekierski, J.R., et al., Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol, 2011. 106(3): p. 508-14; quiz 515.

[8]Bernardo, D., et al., Is gliadin really safe for non-coeliac individuals? Production of interleukin 15 in biopsy culture from non-coeliac individuals challenged with gliadin peptides. Gut, 2007. 56(6): p. 889-890.

[9]Palova-Jelinkova, L., et al., Gliadin fragments induce phenotypic and functional maturation of human dendritic cells. J Immunol, 2005. 175(10): p. 7038-45.

[10]De Palma, G., et al., Effects of a gluten-free diet on gut microbiota and immune function in healthy adult human subjects. Br J Nutr, 2009. 102(8): p. 1154-60.

[11]Yu, Q.H. and Q. Yang, Diversity of tight junctions (TJs) between gastrointestinal epithelial cells and their function in maintaining the mucosal barrier. Cell Biol Int, 2009. 33(1): p. 78-82.

[12]Fasano, A., Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation Living Life on the Edge of the Wall. American Journal of Pathology, 2008. 173(5): p. 1243-1252.

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