The gluten-free craze continues, despite a lack of evidence that anyone other than the 1% of the population who have true Celiac disease, are harmed by gluten or benefit from removing it from their diet.

The controversy remains over the questionable existence of non-celiac gluten sensitivity (NCGS). These are people who do not have Celiac disease, which is an autoimmune reaction to gluten and is diagnosed primarily through the presence of anti-gliadin antibodies in the blood. Gluten is a protein in wheat and similar grains, and gliadin is one of the protein components of gluten. Some patients with gastrointestinal symptoms who test negative for Celiac disease still feel their symptoms are worsened by gluten.

This, in turn, has led to a gluten-free fad as part of the overall clean-eating movement, with gluten being demonized as a “bad” food ingredient that everyone should avoid.

A 2017 systematic review, however, found that studies looking at subjects with possible NCGS being challenged with gluten in a blinded fashion did not show any reliable symptoms. More recent studies have focused on the Salerno Experts’ Criteria – this is a procedure to remove wheat and gluten from the diet of those suspected with NCGS, then rechallenge them to see if symptoms return. There are some positive preliminary results with this protocol, but this the evidence is insufficient to conclude that NCGS is a distinct entity. A 2019 review gave this summary:

There are limited studies estimating the prevalence of NCGS using this study design. The existing studies have variable results likely due to the lack of a uniform diagnostic criterion, a great deal of dependence on the patient’s perception of symptoms and a large nocebo effect in existing studies. In clinical practice, a single blind placebo-controlled rechallenge trial has been recommended for diagnosis. The pathogenesis of NCGS is unclear and there is no known biomarker or diagnostic histologic lesion for this condition.

This situation warrants clinical and scientific caution. It is also a good example of why an SBM approach to such questions is so important. The clinical data is mixed and often subjective. In order to know that a clinical phenomenon is actually real, we would like to see multiple independent lines of evidence. When they are consistent lacking, that should raise skepticism.

In this case, when we look at the gastrointestinal lining of those with presumed NCGS we do not see any consistent pathological changes. We have found not markers in the blood. And challenge experiments show preliminary and mixed results.

This does not mean that NCGS does not exist, and certainly does not mean that patients with possible NCGS do not have real symptoms. What it means is that we do not know if NCGS exists, and we do not know why those patients have the GI symptoms they do. At present NCGS is a hypothesis, and it is a particularly shaky one given the current state of evidence. This means we need to remain humble and open-minded. There is a risk to prematurely settling on a hypothesis before it has been clearly demonstrated.

The risk of premature acceptance is particularly great in medicine. The very belief in a disease can easily take on a life of its own. The putative disease becomes a reality filter, a lens through which vague, heterogeneous, and poorly understood symptoms are viewed. Treatments, practitioners, and markets catering to the alleged disease emerge. Patients with their own support groups and organizations also take root. The entire enterprise is driven by placebo effects and questionable research nibbling around the edges of the core question but never answering it – is this entity real? And of course, those with questionable ethics exploit the situation, and do their best to portray the completely appropriate and even necessary lingering skepticism among experts as a conspiracy.

But keeping that skepticism alive is vital. It is the only way ultimately to the truth. We also have to keep in mind that if we are on the wrong track with NCGS then we are missing the real underlying cause of the symptoms of those who believe they have NCGS. There are already other hypotheses, such as sensitivity to some other component of wheat, or perhaps FODMAPs (fermentable, oligo-, di-, monosaccharides, and polyols). There is probably a reason the ducks are not all lining up. We need to discover what that reason is.

It is still also possible that NCGS is real, but that we simply have no idea what the true mechanism is. Finding that mechanism will be immensely helpful in confirming that NCGS is a distinct clinical entity, understanding it, and ultimately treating it.

To be clear, we don’t need a known mechanism to know that a disease is real. What we do need is a critical mass of evidence, but the balance of different types of evidence can take many forms for different diseases. We could, for example, have an iron-clad clinical syndrome – clear objective signs and symptoms that are fairly homogeneous with a predictable demographic and natural history. We could also have objective pathological markers, in the blood, on biopsy, on imaging, with genetic testing, or some physiological test. Some combination of clinical and pathological factors should lead to a reliable way to make a diagnosis, with good intra- and inter-rater reliability (something which is considered necessary for external validity – meaning that the diagnosis is real).

Finally, if all of this leads to an objectively effective treatment, that closes the loop on our understanding and also helps confirm we are on the right track.

For NCGS we have none of this. We have a vague and heterogeneous clinical syndrome without any objective markers and no clear response to any intervention. Again – none of this proves a negative. It means we don’t know, and we should continue to research other options.

It’s also possible that NCGS is a “garbage pail diagnosis”. This means it is a label applied to many different conditions that we currently don’t understand. If you have GI symptoms and we don’t have a diagnosis, then we throw it in the pail with everything else and call it NCGS. Such diagnoses, however, are better defined as clinical syndromes (like fever of unknown origin or chronic fatigue syndrome) rather than a presumed and unproven cause. The premature label biases our thinking, and the public’s perception.

In any case, this seems like a nut we will eventually crack. It remains an area of active research, and there is significant skepticism regarding NCGS among experts. That skepticism is good, and will serve well in guiding further research.


Posted by Steven Novella

Founder and currently Executive Editor of Science-Based Medicine Steven Novella, MD is an academic clinical neurologist at the Yale University School of Medicine. He is also the host and producer of the popular weekly science podcast, The Skeptics’ Guide to the Universe, and the author of the NeuroLogicaBlog, a daily blog that covers news and issues in neuroscience, but also general science, scientific skepticism, philosophy of science, critical thinking, and the intersection of science with the media and society. Dr. Novella also has produced two courses with The Great Courses, and published a book on critical thinking - also called The Skeptics Guide to the Universe.