Wheat Sensitivity: A New Study Shows It’s Not in Your Head, It’s in Your Gut

Wheat Sensitivity: A New Study Shows It’s Not in Your Head, It’s in Your GutTens of thousands of us go to the doctor every year complaining of varied and vague symptoms that we swear crop up every time we eat bread with dinner. And generally, what we get is a mix of reactions from mild amusement to an unceremonious shooing from the doctor’s office.

But according to a new study out of Columbia University Medical Center – one of the first true controlled trials of wheat sensitivity – those symptoms may not be in your head.1

In fact, there may be very real and testable biomarkers of the condition.

The study authors found “the presence of objective markers of systemic immune activation and gut epithelial cell damage in individuals who report sensitivity to wheat in the absence of celiac disease.”1

To understand just how significant that is, we need to take a step back and look at the somewhat uninspiring history of wheat sensitivity research, also known as Non-Celiac Wheat Sensitivity (NCWS).

The “non-celiac” part of the name shouldn’t be overlooked, because by contrast, celiac disease may very well be the most researched and fully understood autoimmune condition in existance.2-5 A search on Thomson Reuters lists 20,781 studies and reviews alone.
But NCWS, Celiac’s forgotten little sibling, has remained far more elusive.

Past research was limited mostly to a broad categorization of symptoms6 that resulted in a poorly defined condition. The number of sufferers is still unknown, though recent estimates put it higher than celiac disease (which is one percent of the population.)1 Even the cause/s is/are unknown. Gluten plays a key role, but other players such as short-chain carbohydrates may also affect the disease.1,7

Many, even in the science community, question whether NCWS exists at all.8,9

Only in the last few years have there been proper randomized control trials of NCWS. However, these studies focused primarily on how a gluten-free diet affects symptoms such as diarrhea, bloating, fatigue, and irritable bowel syndrome (IBS).7, 10-13 Real testable biomarkers for the condition generally weren’t identified.

That is until the Columbia University study led by Melanie Uhde was published this summer.1

The researchers divided participants into four groups. Eighty NCWS sufferers who ate whatever they wanted. Another 20 NCWS patients who removed wheat, rye and barley from their diet for six months. Forty patients diagnosed with celiac disease and 40 healthy controls.

All subjects were tested for markers of intestinal damage and system-wide inflammation. Not only did the NCWS groups test positive for both (Figures 2 and 3 below)1 but the profile for NCWS was different from both celiac disease and the healthy controls indicating that NCWS is a distinct condition.

It is important to point out that theories about how wheat could break down the gut barrier and cause chronic inflammation are not new. In fact, last year I wrote a four part series detailing both and explaining how they ultimately lead to disease.14
What is exciting about this study, is that it provides the first clear biological evidence of these changes in a select group diagnosed with wheat sensitivity.

Gut Barrier Breakdown

To see if there was damage to the intestinal barrier, the researchers measured levels of fatty acid-binding protein 2 (FABP2) which is rapidly released after epithelial cell damage (the cells that line the gut.)  

FABP2 was elevated in Celiac’s and NCWS but not healthy controls (figure 3):1

Unlike the celiac participants, intestinal biopsies from the NCWS group showed no signs of damage. This is consistent with past research on wheat sensitivity.15 The researchers hypothesized that the damage may be in other regions besides the duodenum (where biopsies are typically taken.) FABP2 is released primarily in the jejunum, lending credence to this theory.

The study authors did not attempt to explain how wheat was causing damage to the gut. However, a zonulin-mediated mechanism has already been heavily researched by Alessio Fasano.4, 16-19 You can read more about it here.

Microbes in the Gut Gain Entry

Our guts are exposed to billions of foreign microbes every day. As I wrote about previously, controlling this barrier is so important that much of our immune system evolved around this task.20-23

When that barrier breaks down, microbes get into circulation and the immune system gets inflamed. Literally.

Uhde and her group wanted to see if the intestinal damaged indicated by elevated FABP2 were causing bacterial translocation – a fancy term for foreign bacteria getting past the intestinal defenses.

They measured circulating levels of sCD14 and LPS Binding Protein (LBP). Both molecules bind lipopolysaccharide (LPS), a key protein found only on foreign bacteria (the bad kind.) So, sCD14 and LBP increase when foreign bacteria gets into the body.

sCD14 and LBP were highly elevated in NCWS subjects (figure 2 above.)

Figure 3 also shows that the increases in sCD14 and LBP correlated strongly with increases in FABP2. This is an important indicator that the foreign bacteria was likely gaining entry due to the intestinal damage.

sCD14 and LBP levels were not as high in Celiac’s or healthy subjects leading the researchers to conclude that the mechanism of NCWS is different. They hypothesized that sufferers may have a defect in their immune system’s ability to fend off bacteria at the intestinal border.

To confirm their results, Uhde’s team tested two other known markers of bacterial translocation – EndoCAb and antibodies to flagellin. Both were elevated in NCWS.

Chronic Inflammation… That Can Be Reduced with a Dietary Change

The researchers warn that if this bacterial translocation is constant, it can lead to a rise in CD14+ macrophages, elevated levels of the transcription factor NFK-β and proinflammatory cytokines.

Over time this chronic inflammatory state can lead to serious conditions.23-30 You can read more about how that happens here.

The question is whether a dietary change can slow or even reverse this trend.

The researchers tested a second group of NCWS sufferers who were placed on a diet free of wheat, rye, and barley for six months. At the end of the intervention, serum concentrations of LBP, sCD14, FABP2, EndoCAb and antibodies to flagellin had all dropped. Subjects also reported a significant reduction in their symptoms.

So it would appear that the better energy and digestion they felt when they choose to pass on the pre-dinner bread wasn’t just in their heads.


[1] Uhde, M., et al., Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut, 2016.

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

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

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

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

[6] 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.

[7] Biesiekierski, J.R., et al., No Effects of Gluten in Patients With Self-Reported Non-Celiac Gluten Sensitivity After Dietary Reduction of Fermentable, Poorly Absorbed, Short-Chain Carbohydrates. Gastroenterology, 2013. 145(2): p. 320-+.

[8] Lebwohl, B. and D.A. Leffler, Exploring the Strange New World of Non-Celiac Gluten Sensitivity. Clin Gastroenterol Hepatol, 2015. 13(9): p. 1613-5.

[9] 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.

[10] Vazquez-Roque, M.I., et al., A Controlled Trial of Gluten-Free Diet in Patients With Irritable Bowel Syndrome-Diarrhea: Effects on Bowel Frequency and Intestinal Function. Gastroenterology, 2013. 144(5): p. 903-+.

[11] Carroccio, A., et al., Non-Celiac Wheat Sensitivity Diagnosed by Double-Blind Placebo-Controlled Challenge: Exploring a New Clinical Entity. American Journal of Gastroenterology, 2012. 107(12): p. 1898-1906.

[12] Wahnschaffe, U., et al., Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome. Clinical Gastroenterology and Hepatology, 2007. 5(7): p. 844-850.

[13] Di Sabatino, A., et al., Small Amounts of Gluten in Subjects With Suspected Nonceliac Gluten Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. Clinical Gastroenterology and Hepatology, 2015. 13(9): p. 1604-+.

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

[15] Elli, L., L. Roncoroni, and M.T. Bardella, Non-celiac gluten sensitivity: Time for sifting the grain. World J Gastroenterol, 2015. 21(27): p. 8221-6.

[16] Fasano, A., et al., Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro. J Clin Invest, 1995. 96(2): p. 710-20.

[17] 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.

[18] 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.

[19] Fasano, A., Intestinal zonulin: open sesame! Gut, 2001. 49(2): p. 159-62.

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

[21] 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.

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

[23] Smith, P.D., et al., Intestinal macrophages and response to microbial encroachment. Mucosal Immunol, 2011. 4(1): p. 31-42.[24] 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.

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

[26] 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.

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

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

[29] 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.

[30] 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.

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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“3” Comments

  1. I just wanted to add my personal experience here that probably goes along with some of the research discussed in this article. I was experiencing GI issues that were often explained a IBS-D. I often was placed on meds to combat this (Bentyl, for example), and it worked a little bit. Nothing got close to curing me, but at the same time I wasn’t interested in a life-long commitment to a drug. I changed PCPs, and he suggested 1) get a food allergy test, and 2) visit a GI doctor. First I visited the GI doctor, who confirmed I needed to get a food allergy test, but he also suggested scoping my stomach and intestines. The scopes proved everything was in proper working order with a bit of acute inflammation. The food allergy test, though, was the enlightening part. I had slightly elevated levels of IgE (in the range of 1.5-2.5 kU/L) for wheat, barley, oat, rye, tomato, and peanut. Nothing else in the test tipped the scale. These are all things I had been eating all my life, and I never suspected an allergy because I never had the typical swelling/redness/hives reaction you might expect from a peanut allergy or a bee sting. Suffice to say, I’ve been trying hard to avoid all of these food since then. And the symptoms have vastly improved. Not gone, mind you, but I don’t worry about where the bathroom is anymore.

    • Thanks for sharing your experience Jason. It would be very interesting to monitor your symptoms while strictly avoiding the offending foods for at least a month. I know this can be very challenging, but do get back to us with what transpires if you are able to implement a complete elimination of the foods.

  2. It’s been confirmed what we already knew and your 4 part series brilliantly enlighted.
    I’ve been thinking exactly the same and I’m a bit surprised that the extensive research about zonuline by Fasano has not been taken into account. The authors claimed that the mechanism underneath the leaky gut is not known but Fasano already explained very well and I don’t know whether they are aware about it.
    Moreover, the 2015 study guided by Hollon, shows once again that gliadin triggers leaky gut in everyone, with the “healthy” control group showing even more leakiness than celiacs in remission following a GFD.
    It means that more or less it affects all of us, and the harm depends on immune system, biome, etc..

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