Gluten is the main structural protein of wheat and related cereal grains. The two best-known diseases related to gluten exposure are a wheat allergy and celiac disease. In both conditions the reaction to gluten is mediated by T-cell activation (adaptive immunity) in the gastrointestinal mucosa. However, a wheat allergy is defined by the IgE-gluten interaction that triggers a release of chemical mediators, such as histamine, whereas celiac disease is defined by an autoimmune response to gluten exposure.
It is now recognized that non-celiac gluten sensitivity (NCGS) represents a third disease in which neither allergic nor autoimmune mechanisms are involved. The problem is that the NCGS clinical picture is heterogeneous and not specific, including intestinal (diarrhea, constipation, bloating, nausea, and epigastric pain) and extra-intestinal (lack of well-being, anxiety, tiredness, fibromyalgia, chronic fatigue, foggy mind, and headache) symptoms. Indeed, the exclusion of celiac disease or a wheat allergy and a favorable response to a gluten-free diet are the main parameters used to identify this condition, which lacks specificity and is subject to the risk of a placebo effect.
In order to help single out NCGS patients in the “real-life” setting of gastroenterological services, Elli et al conducted a 2-phase multicenter, double-blind, placebo-controlled cross-over trial involving 140 adults routinely attending gastroenterological outpatient clinics throughout Italy.
These patients were currently following a gluten-containing diet and had gastrointestinal functional disorders such as irritable bowel syndrome, functional dyspepsia, or other unspecified functional gastrointestinal symptoms. However, none had celiac disease, a wheat allergy, inflammatory bowel diseases, or autoimmune diseases. All reported a general wellbeing of less than 4 on a scale of 0-10 (0 being extremely poor satisfaction and 10 very high satisfaction).
Phase 1: Down the rabbit hole The gluten-free diet
All the patients at this point filled out a bunch of symptomatic questionnaires regarding health, life satisfaction, and severity of symptoms. They were then asked to follow a gluten-free diet for three weeks with the help of flyers describing it and advise to read food labels. Questionnaires were repeated at the end of the three weeks.
Overall, six individuals decided it was okay to interrupt their diet with social commitments, leaving 134 patients who correctly remained gluten-free. Of these, 75% showed improvement in general wellbeing of more than 3 and were deemed “responders” (remember, only those with a baseline rating of 4 or less were enrolled, meaning an increase of 3 or more corresponds to a minimum improvement of 75%). The other 25% of patients were deemed “non-responders.”
In accordance with improved general wellbeing, the responders also showed significant improvements compared to baseline in physical and mental quality of life, abdominal pain, stool consistency, bloating, post-meal fullness, early satiety, epigastric pain, other symptoms, and global satisfaction (figure 1).
When the post gluten-free diet scores between the responders and non-responders were compared, however, only some of the aforementioned scores were significantly different between the groups. The reason being because the responders started with a markedly higher baseline score, meaning that the substantial improvement simply returned them to non-responder levels. This supports the differentiation between responders and non-responders, as we would expect the former to have worse symptoms to begin with.
Also of note is that the non-responder group did show significant improvement vs baseline for epigastric pain and global wellbeing. Although, this is likely to be a placebo effect or some type of bias related to being enrolled in this type of study. There were no reported adverse events.
Phase 2: How far did you fall? The gluten challenge
Among the responsive patients, 98 underwent the double-blind placebo-controlled gluten challenge (three refused because they were scared of symptom relapse). In a crossover design (meaning all patients did both interventions), the patients were randomized to consume seven capsules per day (4 at lunch and 3 at dinner) that contained gluten (0.8 g per cap; 5.6 grams per day total) or rice starch (placebo). The amount of gluten (5.6 g) is the equivalent of 80 grams (~3 ounces) of pasta. All the patients had to continue eating a gluten-free diet during this time, and there was a seven-day washout period between the interventions.
Overall, the patients as whole reported a greater deterioration of their wellbeing during gluten than during placebo administration (figure 2). However, only 28 patients were found to show signs of a symptomatic relapse during the gluten challenge (change in general well-being of more than 3, similar to defining the “responsive” group during phase 1).
This included a reduction in both physical and mental quality of life, as well as a return of many symptoms that were shown to improve in response to a gluten-free diet (figure 3). No demographic, clinical, or biochemical factors (iron, transaminases, and CRP) were found to be associated with the gluten challenge response.
Yet, 14 patients also showed a response to placebo treatment, indicating a possible nocebo effect. Because all patients completed both interventions, it stands to reason that these patients reacted to the gluten pills as well, meaning that about 14 patients can be considered truly gluten-sensitive. Importantly, no carry-over or order effects were noted.
NCGS exists, but you needn’t have it to benefit
This study demonstrates that roughly 14% of individuals who experience a symptomatic benefit from going gluten-free may actually have NCGS. The other patients may have shown a benefit with a gluten-free diet simply because of the elimination of other bioactive components of wheat and related cereals (e.g., FODMAPs) that are also excluded.
Another possibility is that they were consuming more gluten than the challenge provided and there may very well be individual threshold levels for the amount of gluten that can be tolerated. Or possibly the administration of gluten as a capsule did not reflect common eating and cooking practices around gluten ingestion. Can we say a response to a capsule and a slice of bread would be similar?
Regardless of why the patients benefited, isn’t it the benefit that matters? If going gluten-free makes your life better, then who cares if it is actually the gluten component of wheat that is causing problems. Certainly we do need to identify defining criteria for NCGS so as to ensure that some people don’t go on an unnecessary diet that may be inconvenient to them. But that is the crux – that is may be inconvenient. If a person feels betters on a gluten-free diet and isn’t inconvenienced by it, then why shouldn’t they follow it? We all have our dietary patterns and preferences to suit our lifestyles, and maybe a gluten-free diet is one of theirs.
In the end, the 75% positive response rate to going gluten-free is intriguing. Again, it could be owed to any number of things unrelated to gluten per se, but if you experience GI problems then consider giving it a shot.