Natural “Pesticides” in Wheat: Is There a Role in Gluten Sensitivity and Celiac Disease?
By: Peter Olins, PhD on December 19, 2012
The critical role of wheat gluten in celiac disease is well-known, but it is not clear if other components of wheat might cause undesirable health effects. Non-celiac “gluten sensitivity” is becoming more accepted by clinicians, but in reality it hasn’t been proven if this is really an effect of gluten, or if it is caused by other substances in wheat.
The latest paper by Y. Junker and co-workers studied proteins in wheat called “amylase-trypsin inhibitors” (ATI), which as act as natural pesticides. They found that ATIs trigger “innate” immune responses that are similar to those caused by gluten. It is possible that consuming ATIs might be important in the early stages of celiac disease. Also, since ATIs provoke an immune response in the intestinal tissues of non-celiacs, it is conceivable that ATIs might also be the culprit in non-celiac gluten sensitivity.
Both “Innate” and “Adaptive” Immunity are Important in Celiac Disease
This is a simple defense system designed to protect us against invasive organisms, such as bacteria. It is an ancient system, and is even present in primitive organisms like insects. In the human intestine, the innate immune system recognizes simple molecular patterns on bacteria, and mounts an immediate protective response. It’s really our first line of defense in determining “friend or foe”. This molecular recognition process involves proteins, called toll-like receptors (TLRs), which I will describe later.
This mechanism evolved much more recently, and involves both antibodies and T-cells that recognize very specific molecular surfaces. Adaptive immunity involves many steps, and initially takes days or weeks to develop. The big advantage is that the immune system “remembers” previous encounters, so that repeat infections can be warded off very rapidly.
Underlying all of this is the concept of immune “tolerance”. The body needs to be able to identify its own proteins as being safe, but still be able to detect potential threats from the outside world. Normally, we have immune “tolerance” to proteins in our food, and to our own proteins. But somehow, for the very small fraction of people that develop celiac disease, this tolerance breaks down, resulting in a dramatic immune response to both dietary gluten and one of our own proteins (tissue transglutaminase 2). The reason for this breakdown of tolerance is unknown.
One current model for celiac disease is that it occurs in two steps. First, there is an innate immune response to gluten which primes the immune system. Next, specific peptides within gluten provoke an adaptive immune response, which ultimately leads to an inappropriate reaction to certain human proteins. Activation of TLR4 is thought to play a role in priming the adaptive immune system.
Non-Celiac Gluten Sensitivity
One theory for non-celiac gluten sensitivity (NCGS) is that this is an innate immune response to gluten—the only difference is that people with NCGS do not go on to develop full-blown celiac disease (Ref. 1).
As I discussed in a previous blog (Ref. 2), most of the preliminary research on non-celiac gluten sensitivity has involved putting people on a gluten-free diet, and monitoring symptoms. The problem is that these diets are not really specific for gluten, but are really just wheat-free. So, it is a still an open question whether this condition is really caused by gluten or something else in wheat. “Wheat sensitivity of unknown origin” might be a more accurate description.
Ref. 1: Bernardo, et al. Is gliadin really safe for non-coeliac individuals? Production of interleukin 15 in biopsy culture from non-coeliacs challenged with gliadin peptides. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1954879/
Natural Pesticides Are Common in Plants
We tend to think of pesticides as being chemicals that we apply to crops to protect them from insects. In reality, millions of years ago, plants developed a wide range of defense mechanisms to prevent being eaten by insects or animals, or to thwart attacks by fungi and other diseases (Ref. 3). This is especially true for the protection of seeds, since these are essential for the propagation of the species.
Many of these natural pesticides are also unpleasant to humans, and a key part of plant breeding over the past few thousand years has been to reduce the amount of these irritants, and make the foods safer and more palatable. One simple example is the high levels of irritants in such foods as chile peppers or onions, which causes a burning sensation when consumed. (Of course, some people choose to ignore the warning signals of these irritants!).
In addition to irritants, plants produce a wide range of different biological pesticides that prevent seeds from being digested by pests. For example, there is a large family of proteins called “amylase-trypsin inhibitors” (ATI’s). ATI proteins block the enzymes that are normally used to digest starch (amylase) and protein (trypsin) in food, and are toxic to many insects and other pests. Many seeds, including wheat, contain a wide range of enzyme inhibitors, such as ATI.
Ref. 3: Ames, BN, et al. Dietary pesticides (99.99% all natural) Proc Natl Acad Sci U S A. 1990 Oct;87(19):7777-81.
Latest Results: ATI’s Stimulate the Human Innate Immune System
In the latest paper by Y. Junker and co-workers (Ref. 4), they found that wheat ATI is not only an enzyme inhibitor, but was also recognized as being “foreign” in the intestine, activating the innate immune system. Two ATI proteins were purified from wheat, and tested for their biological activity on three types of human immune cells: macrophages, monocytes and dendritic cells. In all three cases, ATIs provoked an immune response.
To investigate the mechanism, ATIs were fed to mice, and the researchers detected an inflammatory response in cells from both blood and intestine. The response in the intestine was shown to be dependent on the “Toll-Like Receptor 4″ (TLR4), which normally provides a defense against bacteria.
To test the relevance of this to humans, the two wheat ATIs were tested for their activity on human intestinal biopsy samples. The authors found a similar stimulation of the innate immune system as they had seen in mice. Remarkably, this effect was seen with the biopsy samples from both celiac patients and normal subjects. The effect of ATIs on the tissue from normal people was unexpected. While there is no direct evidence at the moment, the authors speculate that this newly described response to ATI might actually be the trigger for non-celiac gluten sensitivity.
Ref. 4: Junker, Y, et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. http://www.ncbi.nlm.nih.gov/pubmed/23209313 J. Exp. Med 2012, Dec. 3.
Amylase/Trypsin Inhibitors Also Present in Many Other Seeds
As I mentioned earlier, many plants produce a variety of natural pesticides. In addition to the three grains important in celiac disease (wheat, barley and rye), ATIs are also found in a wide range of other seeds used for food—including soy, quinoa, buckwheat, peas, and corn. In a recent abstract by Zevallos and co-workers (Ref. 5), ATIs were purified from a wide range of food seeds. When the ATIs were added to a cell culture assay, there was an increase in the production of interleukin 8, which is an indicator of innate immune system activation. (A similar response has been seen in a different study, triggered by gluten). The highest interleukin 8 stimulation was found for wheat, barley and rye ATIs, but a significant effect was also found for the other seeds tested. This is a very preliminary result, but it is conceivable that this might account for the intolerance that a few people have to a variety of seeds other than the familiar wheat/barley/rye trio.
Ref. 5: Zevallos, V. et al. 2012. Purifikation, Charakterisierung und biologische Wirkungen von alpha-Amylase-/Trypsininhibitoren aus Pflanzen, Effektoren von intestinalen TLR4 bei Zöliakie https://www.thieme-connect.com/ejournals/abstract/10.1055/s-0032-1323857
This research is still in its early stages, and much more work will need to be done to determine if there is a cause-and-effect relationship between ATIs and human intestinal health. However, the potential implications of this work are intriguing:
- While most people can eat wheat without any problems, the non-celiac “gluten sensitivity” found in some people might actually be caused by ATIs rather than gluten.
- The research supports earlier research suggesting that ALL people might have some level of reaction to wheat, not just celiacs.
- It is possible that stimulation of the innate immune system by ATI could be an early trigger for celiac disease. If this true, then it opens up the possibility of a completely different set of approaches for preventing or treating celiac disease, in parallel with the current focus on gluten.
- Long-term, it might be possible to breed varieties of wheat that have reduced ATI content, and therefore might be safer.
- The significance of the presence of ATIs in a variety of seeds other than wheat is not known. However, it is conceivable that it might account for the mysterious sensitivity to these seeds that has occasionally been described.
These ideas remain speculative at the moment. However, in my opinion, this work could represent a major breakthrough in the research on gluten sensitivity and celiac disease!