The Wheat Series Part 1: Wheat and the Immune System

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.



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[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.

About Trevor Connor, M.S.

Trevor Connor, M.S.Trevor Connor was Dr. Loren Cordain’s last graduate student at Colorado State University. His research with Dr. Cordain focused on the effects of a Paleo style diet on autoimmune conditions. Their pilot study included close to 60 volunteers with diverse conditions ranging from Crohn’s Disease, to Multiple Sclerosis to Hashimoto’s Thyroiditis. The results were very promising, including all eight Crohn’s subjects going into remission on the Paleo Diet.

Trevor started working with Dr. Cordain in 2010, soon after retiring as a Professional Cyclist. At 38, he felt it was time to hang up the bike. Trevor had studied traditional sports nutrition for over a decade and was admittedly very reluctant to accept the Paleo Diet. But after experimenting with the diet himself, Trevor was able to return to the Pro Peloton at 40, getting Top Five’s in several races and establishing himself as the top ranked 40+ rider in the country for several years running.

Trevor now writes the Coaching Section of the international cycling magazine Velo, has his own coaching business, and recently managed the semi-Professional cycling team Team Rio Grande who’s alumni include Teejay Van Gaarderen, a top five finisher at the Tour de France and multiple national champions.

Trevor is currently working on publishing several studies and reviews on the effects of wheat on the digestive immune system. Recently, he moved back to Canada so his wife could pursue her dream of making the 2016 Olympics in pole vaulting (as a Paleo Dieter and ranked top 10 in the country in her mid-30’s.)

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“4” Comments

  1. Trevor

    Thanks for your referenced articles, as a family doc, I can never find in Canada ( Quebec) that type of science !
    Use it almost every day at the office !

    And also, thanks for your gréât column in VÉLO news, I just realised who you are !

  2. If I buy hard wheat, non irradiated, Non GMO, tracable, etc. Can I grind it myself and be alright or am I missing the whole point. It seems to me that if I could be assured of the wheat being clean, no chemicals, etc. it would be good. I’ve been doing the Paleo diet for about 4 months. I have lost a small amount of wheat but I am more concerned with how healthy I am. I am 79 years old and a type 2 diabetic with some digestion problems and an ever present UTI problem (which is getting better). I just miss my homemade bread. The nut flours are o.k. but they just aren’t the real thing. Can you answer my question?

  3. How long does it take for one’s immune system to get better? I had been eating strict paleo for 4 years and feeling good in most ways, but I got 2 very bad colds within three months of each other, with the second one turning into pneumonia; something I’ve never had in my life. As crazy as it seems, I was catching anything going around when I was being the most careful about my diet and never allowing grains or dairy to touch my lips. It’s confusing, to say the least…

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  5. Thank you!! such a helpful detailed explanation of how wheat has been plaguing me and countless others in my life!! It’s wonderful to have a scientific explanation I can share with loved ones to explain why they are not “fine”, as you say, consuming wheat.

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