Last Updated on October 21, 2016 by Patricia Carter

SUMMARY.  This post looks at other ways beyond Celiac and NCGS, that wheat can affect EVERYONE and includes new groundbreaking research being presented in Vienna.  The bottom line:  Move over gluten, ATI wrecks guts too, and… we have a new picture of what the inflamed gut looks like!  ATIs, or amylase-trypsin inhibitors, are non-gluten proteins in wheat.  ATIs activate specific types of immune cells [toll-like receptor 4] in the gut and other tissues.   ATIs can trigger gut immune reactions that can spread to other tissues in the body.  How bad can this get?  “ATIs can lead to the development of inflammation in tissues beyond the gut, including the lymph nodes, kidneys, spleen and brain.   ATIs can worsen the symptoms of pre-existing inflammatory based conditions like RA, MS, asthma, lupus, IBD, and non-alcoholic fatty liver disease…”   The final big hit:  “ATIs may contribute to the development of non-coeliac gluten sensitivity (NCGS).”  No wonder so many feel better ditching wheat since you knock out both gluten and ATIs AND decrease inflammation not just in the gut, but systemically!  For an example, IBD and neurological  association to ATI is discussed below!  What about the  non-gluten containing staples you may be consuming?  Those displayed no or little of the toll like receptor 4 stimulating activity whereas ATIs displayed much! 

Move over gluten, ATI wrecks guts too, and the damage goes beyond the gut!

This is cutting edge research, presented at the Opening Plenary Session at UEG Week Vienna 2016, which began October 15 and ran to Oct 19, 2016!  You can listen live to these expert researchers, just sign into UEG.  Obviously I have been!  Regarding archiving content, I honestly don’t know UEG policy.

Proteins in wheat.  There are a lot of different proteins in wheat and they are classified into groups, known as gliadins, glutenins, albumins and globulins.  

Up to now, its been all about gluten (gliadin to be exact) and Celiac Disease and Non-Celiac Gluten Sensitivity (NCGS).  Celiac has been well characterized over the last 4 decades.  NCGS is the relative new comer.  But with both conditions, what has not been known was what and how the innate immune system interacted.  Researchers have been on the look out for the additional modulating factors, including cereal stimulants, of innate immunity, affecting signaling receptors for celiac disease, but until now, have not found the answer(s).

Now enters ANOTHER NEWLY FOUND WHEAT PROTEIN, a non-gluten wheat protein, called amylase-trpsin inhibitors (ATIs), that seems to be the what and how for activation of the innate system for wheat.  ATIs are a subset of the albumin protein in wheat; ATIs are enriched in wheat and related cereals.  

What does ATI innate immune activity do to the gut?

In sum,  ATIs causes inflammation at the gut level that extends to inflammation beyond the gut including lymph nodes, spleen, kidney, and brain.  When ATIs are fed to mice with autoimmunes or allergies, more severe disease and stronger antigen-specific adaptive immunity developed.  Researchers agree that clinical studies are needed to determine whether this observation applies to humans with chronic inflammatory diseases.  That would mean that consumption of wheat ATIs could worsen conditions such as RA, MS, IBD, asthma, lupus, alcoholic fatty liver disease, etc.  ATIs also may contribute to the development of NCGS which includes association to IBS along with keen interest in associations to neurological conditions like autism, depression, AD, PD, etc.

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The Studies.

From the 2015 Schuppan, et al paper, Non-celiac wheat sensitivity: differential diagnosis, triggers and implications:

• ATIs  are highly protease resistant [resist digestion] and activate the toll-like receptor 4 (TLR4) complex in monocytes, macrophages and dendritic cells of the intestinal mucosa.
• Oral ingestion of ATIs costimulate antigen presenting cells and promote T cell activation in celiac disease, but also in other immune-mediated diseases within and outside the GI tract.
• Consumption of ATIs can lead to the development of inflammation in tissues beyond the gut, including the lymph nodes, kidneys, spleen and brain. Evidence suggests that ATIs can worsen the symptoms of rheumatoid arthritis, multiple sclerosis, asthma, lupus and non-alcoholic fatty liver disease, as well as inflammatory bowel disease.
• ATIs may contribute to the development on non-coeliac gluten sensitivity (NCGS).

Quantifying  ATIs DAMAGE:  Lots of collateral damage,

Says Professor Detlef Schuppan, the studies lead author from the Johannes Gutenberg University, Germany, here and here unless otherwise noted:

•  As well as contributing to the development of bowel-related inflammatory conditions, we believe that ATIs can promote inflammation of other immune-related chronic conditions outside of the bowel.  
• The type of gut inflammation seen in non-coeliac gluten sensitivity differs from that caused by coeliac disease, and we do not believe that this is triggered by gluten proteins.
• Instead, we demonstrated that ATIs from wheat, that are also contaminating commercial gluten, activate specific types of immune cells [toll-like receptor 4] in the gut and other tissues, thereby potentially worsening the symptoms of pre-existing inflammatory illnesses.
• Mice with chronic autoimmune diseases or allergies that ate ATIs at levels equivalent to those of human consumption develop more severe disease and stronger antigen-specific adaptive immunity than controls fed a defined ATI- or gluten-free diet (own Zevallos VF et al, unpublished data ) (Fig.3).—Fasano A, Sapone A, Zevallos V, Schuppan D, Non-celiac Gluten Sensitivity, Gastroenterology (2015), doi: 10.1053/j.gastro.2014.12.049
• In vitro and in vivo studies by Schuppan et al, showed that wheat ATIs induce innate immune responses that activate innate immune cells called monocytes, macrophages, and dendritic cells — major signaling pathway for the TLR4 complex. Feeding of ATIs to mice increased intestinal and systemic release of cytokines and chemokines such as IL8, tumor necrosis factor-α, and CCL2 within 2−12 hrs. Studies of biopsies from patients with celiac disease demonstrated that ATIs increase the gluten-specific Tcell response. —Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4, 2012.
• We are hoping that this research can lead us towards being able to recommend an ATI-free diet to help treat a variety of potentially serious immunological disorders.

Dr. Alessio Fasano, MD is the world renowned celiac expert.   He is totally on-board with the Schuppan described ramifications of ATIs.  This Fasano/Schuppan 2015 paper explains:  

Therefore, ATIs could be long-sought inducers of innate immunity in patients with celiac disease or NCGS. 

—Fasano A, Sapone A, Zevallos V, Schuppan D, Non-celiac Gluten Sensitivity, Gastroenterology (2015), doi: 10.1053/j.gastro.2014.12.049 

From the 2015 Fasano/Schuppan paper, here is the gut with the newly discovered ATI innate activity added:

The ATI innate activator finding is such a game changer, namely that non-gluten proteins are linked to Non-Celiac Gluten Sensitivity (NCGS), that new terminology is now used.  The new terminology is Non allergy-non-celiac wheat sensitivity (NCWS)!  Wheat sensitivity, rather than gluten sensitivity, seems to be a more appropriate term, keeping in mind that other gluten-containing grains like barley and rye can also trigger the symptoms. 

Actually, ATIs are not only in wheat, but we eat so much wheat that we provide a continuous moderate inflammation stimulus to our gut (from the 2015 Fasano/Schuppan paper). 

• Wheat, kamut, barley, rye (the gluten containing cereals) and soy have rich sources of ATI having TLR4-stimulating activities. ATIs can provide a continuous moderate proinflammatory stimulus in our wheat-based diets. The concentration of ATIs in modern wheat is high, accounting for 4%–5% of the total protein in modern wheat  (with gluten accounting for 80%−90%).  Therefore, an adult who consumes an average of 250 g of wheat flour per day will ingest 0.5−1 g of ATIs. —Fasano A, Sapone A, Zevallos V, Schuppan D, Non-celiac Gluten Sensitivity, Gastroenterology (2015), doi: 10.1053/j.gastro.2014.12.049   
• Nearly 1 g of ingested ATIs per day is an amount that is 3-fold higher then in the near East. —excerpted from the Schuppan et al authors response to this commentary, Proinflammatory Wheat Attacks on the Intestine: Alpha-Amylase Trypsin Inhibitors as New Players, read PDF here, 2013.

Non-gluten containing cereals or staples display no or little TLR4 stimulating activity. 

—Non-celiac wheat sensitivity: differential diagnosis, triggers and implications. May 2015.

Tip however:  If you choose gluten-free oats, make it organic to avoid the glyphosate!

• It is only the ATIs of gluten containing cereals that strongly activate TLR4 (unpublished data). —excerpted from the Schuppan et al authors response to this commentary, Proinflammatory Wheat Attacks on the Intestine: Alpha-Amylase Trypsin Inhibitors as New Players, read PDF here, 2013.
• Quinoa, oats, rice, and fermented soy (gluten-free staples) have lower nearly absent [ATI] levels. —Fasano A, Sapone A, Zevallos V, Schuppan D, Non-celiac Gluten Sensitivity, Gastroenterology (2015), doi: 10.1053/j.gastro.2014.12.049. Also from Dr. Zevallos, lead author of the abstract “Isolation of Alpha-Amylase/Trypsin Inhibitors From Various Plants and Their Ability to Activate Innate Immunity in Celiac Disease.”  Sa1309 poster presented at Digestive Disease Week 2012 as cited in —Proinflammatory Wheat Attacks on the Intestine: Alpha-Amylase Trypsin Inhibitors as New Players, read PDF here, 2013.

What all this means is that there is another wheat protein, a non-gluten wheat protein, called ATI, that WRECKS HAVOC IN GUTS TOO.

Other ATI findings:

• The 2012 findings of Schuppan et. al., paper summed:  ATIs are new wheat components, which drive proinflammatory cytokine synthesis in a TLR4-dependent manner, not only in various innate immune cells, but also in duodenal tissues of normal mice and of patients with celiac disease. These data support the notion that wheat products might not only mediate celiac disease, but also contribute to other chronic inflammatory disorders. 
• Importantly, morphological effects of ATIs in the gut are discrete and thus well in line with those previously described in patients with likely NCGS 6,8 . Clinical studies are needed to determine whether this observation applies to humans with chronic inflammatory diseases.—Fasano A, Sapone A, Zevallos V, Schuppan D, Non-celiac Gluten Sensitivity, Gastroenterology (2015), doi: 10.1053/j.gastro.2014.12.049
• Put another way, the Schuppan et al studies suggest that ATI are potent activators of TLR4 and these researchers believe that this interaction, of ATI with TLR4, is a major signaling pathway in innate immune reactions to wheat. [The authors also note] there may still be other gliadin-dependent  signaling pathways but they still remain to be characterized.   —Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4, 2012.
• For those wanting even more specifics:  ATIs stimulate tolllike receptors (TLR4) and proinflammatory cytokines initiating an inflammatory response.  ATIs are strong inducers of innate immune responses in human and murine stimulating monocytes, macrophages, and DCs, and in vitro produces IL-8 and other inflammatory cytokines such as IL-12, TNF, MCP-1, or RANTES.  ATI family members activate the TLR4–MD2–CD14 complex and elicit strong innate immune effects not only in vitro but also in vivo after oral or systemic challenge. Feeding ATIs to C57BL/6J mice resulted in upregulation of proinflammatory cytokines in their duodenal mucosa, which confirms resistance of ATIs to enteric proteases and their stimulatory potential in vivo.—Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4, Dec 2012.

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The B-I-G Picture: Ramifications of ATI on health

This thoughtful commentary, see PDF here, on the 2012 findings of Schuppan et al, explains the significance:  Therefore for the first time wheat components beyond [gluten] gliadins (ie, ATIs), drive innate and inflammatory responses in the gastrointestinal tract…  Importantly, macrophages and DCs, rather than epithelial cells, responded to wheat ATIs via TLR4, thereby inducing the release of proinflammatory cytokines/chemokines and initiating an inflammatory response… [for patients] gluten may induce symptoms similar to functional bowel disorder-like symptoms, and this may take place via ATIs attacking the intestine…  For some individuals the need for GF diet [that knocks out gluten and ATI] may be related to cognitive problems, irritable bowel syndrome, dysbiosis, over consumption of FODMAPs, chronic fatigue, and neurological conditions including depression. For others, gluten intolerance/sensitivity may be due to celiac disease in a latent form.

The 2015 Fasano/Schuppan paper explains that future ATI animal studies will:

• Identify, isolate, and characterize compounds that contribute to NCWS development (ATIs, gluten, or others), most likely to be found in wheat and related staples. 
• Evaluate the effects of those compounds that activate innate immunity, and their effects on concomitant conditions such as autoimmune and metabolic disorders.

Importance of ATI for Inflammatory Bowel Disease (IBD) Patients and lack of clinical translation of ATI-free diet.

Several authors have suggested an association between celiac disease and IBD (J Am Acad Dermatol 1994;31:1050– 1051). Whereas the prevalence of IBD in celiac disease seems to be increasing, the prevalence of celiac disease in IBD is comparable with controls (Scand J Gastroenterol 2007;42: 1214–1220). Anti-Saccharomyces cerevisiae antibodies are known to be positive in about 65% of Crohn’s disease patients. In most patients, anti-Saccharomyces cerevisiae antibodies disappeared during a gluten-free diet, especially in a pediatric population (Eur J Gastroenterol Hepatol 2006;18: 75–78). Interventional studies with gluten- (and thus ATI-) free diets are currently lacking both for ulcerative colitis and Crohn’s disease.  —Proinflammatory Wheat Attacks on the Intestine: Alpha-Amylase Trypsin Inhibitors as New Players, read PDF here, 2013

Importance of ATI for neurologic conditions. Patients and lack of clinical translation of ATI-free diet.

Less frequently, they [celiac and NCGS] present with extra-intestinal manifestations, including fatigue and attention-deficit disorders 25. Of particular interest is the relationship between NCGS and neurologic and neuropsychiatric disorders, including autism, schizophrenia, and peripheral neuropathy 26,27,28.  However, it is not clear how gluten might contribute to these disorders. —Fasano A, Sapone A, Zevallos V, Schuppan D, Non-celiac Gluten Sensitivity, Gastroenterology (2015), doi: 10.1053/j.gastro.2014.12.049

Celiac Disease (CD) and NCGS may lead to a variety of neurologic extra intestinal symptoms, such as gluten ataxia, neuropathy, epilepsy, and depressive and mood disorders [56-58]... silent forms of CD, where fatigue or cognitive problems may be the only symptoms of dietary indiscretion. In a survey of US pediatricians and primary care physicians on the symptoms of CD, only 54% were aware that chronic fatigue, and 46% knew that depression and other mood disorders were related [76]… The autoimmune hypothesis for CD and NCGS associated neurologic disorders is supported by the presence of anti-GAD (glutamic acid decarboxylase) antibodies and anti-ganglioside antibodies [59]. The incidence of CD among peripheral neuropathy patients referred to one specialty center, confirmed by elevated antigliadin or transglutaminase antibodies, was 2.5% [60]. Glutenrelated neurologic dysfunction encompasses a broad spectrum of systemic autoimmune disorders [61].  See Celiac & Gluten Intolerance: A Wellness Perspective for referenced studies.

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Everyone needs answers to these important ATI Questions

Are ATIs a dominant mechanism in patients with celiac disease? Do they contribute to other chronic inflammatory disorders in the gut, such as ulcerative colitis, Crohn’s disease, or other immune-mediated diseases? Do they play a role in certain extraintestinal disorders? Would IBD patients benefit from ATI-free diets? Which diagnostic tools can be developed?  How can the effects of ATIs be blocked? Only via specific ATI-free diets? Or also by specific fermentation or neutralization? Evidence is accumulating that the “pathogenicity of a Western diet” might be influenced by the imbalance of pro and anti-inflammatory dietary factors. In a sense, ATIs can be considered as new proinflammatory dietary components. Exciting times are ahead of us in the field of diet and gastrointestinal disorders.—Proinflammatory Wheat Attacks on the Intestine: Alpha-Amylase Trypsin Inhibitors as New Players, read PDF here, 2013

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Think again if you think you have a cast iron stomach.  The gut is constantly exposed to the environment and in dealing with those demands, it is amazingly complex.  Check out the metabolite complexity and structure of intestinal barrier in the below slides.  To see some of this in action check out this Nature Video YouTube.

Details of the barrier intestinal structure which is  composed of cellular and extracellular elements.

The cellular part is defined by:

• intestinal epithelium (five distinct type of cells, such as stem cells, Paneth cells, enterocytes, goblet cells, and enteroendocrine cells) and the
• underlying lamina propria, which contains DCs (also intraepithelial DCs, IEDCs), macrophages, intraepithelial lymphocytes (IEL), T regulatory cells (T Regs), TCD4⁺lymphocytes (T CD4), B lymphocytes (B), and plasma cells (PCs).

The extracellular component consists in a mucus layer produced by Globet cells, AMPs secreted by Paneth cells, and sIgA dimers released by plasma cells. DCs, dendritic cells; AMPs, antimicrobial peptides; sIgA, secretory ImmunoglobulinA.

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UEG, or United European Gastroenterology

You too can LISTEN LIVE to UEG 2016 Week, link in here.  I don’t know about archive UEG policy.

Who is UEG?  UEG, or United European Gastroenterology, is a professional non-profit organisation combining all the leading European societies concerned with digestive health.  Together, our member societies represent over 22,000 specialists, working across medicine, surgery, paediatrics, GI oncology and endoscopy. This makes UEG the most comprehensive organisation of its kind in the world, and a unique platform for collaboration and the exchange of knowledge.

What is UEG WeeK?  UEG Week is the largest and most prestigious gastroenterology meeting in Europe and has developed into a global congress. It attracts over 14,000 participants each year, from more than 120 countries, and numbers are steadily rising. UEG Week provides a forum for basic and clinical scientists from across the globe to present their latest research in digestive and liver diseases, and also features a two-day postgraduate course that brings together top lecturers in their fields for a weekend of interactive learning.

Conclusion:  It is totally great finding the innate activator for wheat to be the non-gluten wheat protein called ATI!  That it’s stimulation likely extends beyond the gut, to NCGS as well as inflammatory disease conditions is a game changer!  Realize that’s not saying ATI is the lone player in this scenario, but at least it is a start!  There’s more to wheat than meets the gluten eye for sure!

Best in health through awareness,

 

 

 

 

Other links you may be interested in:

• Zevallos V, Weinmann-Menke J, Meineck M et al. Alpha-amylase/trypsin inhibitors (ATIs) accelerate murine systemic lupus erythematosus. Poster presentation at the 16th International Coeliac Disease Symposium, 21–24 June 2015, Prague, Czech Republic. Poster P168.
• Zevallos V, Yogev N, Nikolaev A et al. Consumption of wheat alpha-amylase/trypsin inhibitors (ATIs) enhances experimental autoimmune encephalomyelitis in mice. Oral presentation at the 16th International Coeliac Disease Symposium, 21–24 June 2015, Prague, Czech Republic.
• Junker Y, Zeissig S, Kim S-J et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med 2012;209(13):2395-408.
• Fasano A, Sapone A, Zevallos V et al. Nonceliac gluten and wheat sensitivity. Gastroenterology 2015;148(6):1195-204.
• Schuppan D, Pickert G, Ashfaq-Khan M et al. Non-celiac wheat sensitivity: Differential diagnosis, triggers and implications. Best Pract Res Clin Gastroenterol 2015;29(3):469–76.