Fasano: “NCGS is a reaction of the innate immune system”

There is a growing body of evidence confirming the reality of Non Celiac Gluten Sensitivity (NCGS) as a clinical entity distinct from Celiac Disease (CD) and Wheat Allergy (WA). First described in the 1980s, NCGS has seen a rapid increase in both patients diagnosed and papers published since the initial experts’ consensus conference in London in 2011. Since we have yet to uncover biomarker(s) to definitively diagnose NCGS, there is still a lot of confusion about this condition. Because many of its gastrointestinal symptoms mimic those of Irritable Bowel Syndrome (IBS), NCGS can be mistaken for FODMAPs-induced IBS. However, comparing the two conditions is like comparing apples and oranges.

In the instance of FODMAPS and NCGS, it is important to make sure the terms being used are clearly defined. Reaction to FODMAPS is a true food intolerance, or a non-immune response to foodstuffs, similar to lactose intolerance. Related symptoms caused by the sugars’ fermentation in the colon (either because of a lack of enzymes to properly digest them in the small intestine or because they are ingested in large quantities) are bloating, constipation, diarrhea and other gastrointestinal symptoms often seen in NCGS and CD.

A food sensitivity is an immune reaction to a component in food, typically proteins, which can cause both intestinal and extra-intestinal symptoms. The extra-intestinal symptoms of NCGS, e.g., “foggy mind,” headache, anemia, eczema, joint and muscle pain, tingling in arms and legs, chronic fatigue and behavioral issues such as anxiety and depression, cannot be accounted for by a food intolerance.

When we describe or diagnose NCGS, we do not use the term intolerance, but include NCGS in the spectrum of gluten-related disorders that includes CD and WA. Diagnosis, according to the Salerno Experts’ Criteria from 2015, should be considered in patients with “persistent intestinal and/or extra-intestinal complaints showing a normal result of the CD and WA serological markers on a gluten-containing diet.”

When these patients experience symptoms on a gluten-containing diet, there are recommended steps to follow to determine if NCGS is present. Once CD and WA have been ruled out, the patient is given a double-blind gluten placebo-controlled challenge test. The Salerno Experts’ Criteria offer diagnostic guidelines for patients who have been on a GFD as well as for those eating a gluten-containing diet. Much work remains to be done in the diagnostic arena for this condition, particularly with the confounding component of many patients self-treating on the GFD.

There is also much work to be done to determine the pathogenesis of NCGS. Unlike CD, patients with NCGS do not demonstrate intestinal inflammation or elevation of tTG antibodies. People with NCGS generally have adverse symptoms develop within hours of ingesting gluten, supporting the current basic science evidence that NCGS is a reaction of the innate immune system, and not an allergic reaction or a food intolerance. Some research suggests that the basophils of NCGS patients are not regulated by gliadin. There is an increase in intraepithelial lymphocytes in NCGS biopsies and markers associated with innate immunity.

Wheat ATIs also could play a major role as triggers of the innate immune response in intestinal monocytes, macrophages and dendritic cells, as seen in some in vitro studies. Finally, components of gliadin can induce an immune reaction similar to invading bacteria. In most people, this is not a problem, as the immune system does its job of “cleaning up” the invaders, and there are no lasting ill-effects. For people with a genetic predisposition to a gluten-related disorder, it’s a different story.

Related to the challenge of determining the pathogenesis of NCGS is determining which individuals are most susceptible to developing NCGS and what might trigger its onset. Learning the answers to these questions could lead to the development of therapies to prevent the condition. One likelihood is that there are different triggers, such as an infection, a course of antibiotics, changes in diet and stress, all of which could lead to an imbalance in the gut microbiome, leading to an increased intestinal permeability and NCGS.

In terms of the risks of going gluten-free for a “health conscious” motivation rather than medical necessity, there is no inherent danger in “going gluten-free.” However, problems can arise when the GFD is implemented without the guidance of a registered dietitian to ensure that the patient is receiving the optimal balance of appropriate fibers, minerals and vitamins. It is important to remember that the GFD is a medical intervention, and as such, it needs to be closely monitored to ensure success.


To conclude, there are many unanswered questions about NCGS—how to diagnose and manage it, how it develops, and how many people are affected by this condition globally. It reminds me of where we were in our knowledge of CD nearly 40 years ago. When we can identify and validate biomarkers for NCGS, we will be better equipped to answer some of the mysteries surrounding NCGS.

Fasano, et al., Diagnosis of Non-celiac Gluten Sensitivity: The Salerno Experts’ Criteria: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488826/pdf/nutrients-07-04966.pdf

Bio Alessio Fasano, MD

World-renowned pediatric gastroenterologist, research scientist and entreprenuer Alessio Fasano, M.D., is the W. Allan Walker Professor of Pediatric Gastroenterology at Harvard Medical School and Chief of the Division of Pediatric Gastroenterology and Nutrition at MassGeneral Hospital for Children. His visionary research has advanced international understanding and awareness of celiac disease and gluten-related disorders. In 2000, he and his team discovered zonulin, which regulates intestinal permeability and can play a role in inflammation and autoimmunity throughout the systems of the body. Dr. Fasano recently authored Gluten Freedom to dispel confusion about gluten and how it can affect your health. 



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