Medical education: Gluten intolerance – Intoleranta la gluten


What’s what?

Gluten intolerance or gluten sensitivity is a broad spectrum of diseases that includes celiac disease. Celiac disease is an auto immune condition in which genetically pre-disposed individuals suffer from pain and discomfort in the gut, vitamin deficiencies, fatigue, chronic constipation and diarrhea after ingestion of gluten.

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From: “Gluten-related disorders” by Dr. Schär AG – Dr. Schär AG. Licensed under Public domain

A little bit of history

If you are into bread-making or watch cooking shows, you probably already know that gluten (apart from yeast) is critical in the leavening process of the dough. It provides the dough elasticity, viscosity and thickness. Gluten itself doesn’t help the bread rise, yeast does that. As fermentation occurs carbon dioxide gas is produced by yeast. This gas gets trapped by elastic and viscous web created by gluten. Thereby causing the leavening or the rising of the dough. If you are a bread maker or if you belong to a culture that uses leavened bread then you would prefer wheat with high amount of gluten. You would also want to selectively breed for wheat grains that have higher percentage of gluten in them. Based on this logic one could hypothesize that the process of bread making must have selected for grains with large amount of gluten (this is potentially a fantastic case of gene-culture coevolution; the culture of bread making selects for the increased output of gluten in wheat). Since the process of leavening requires high gluten content, it is not a wild speculation to suggest that percent gluten in wheat used for bread making must have gone up since bread making (leavening) practice was invented.

Is gluten intolerance real?

Celiac disease is real; no one is doubting or challenging that. The debate is around another sub-category of gluten intolerance/sensitivity. Some researchers and many laymen are proposing that non-celiac gluten sensitivity is a real condition. Non-celiac gluten sensitivity is a condition in which you may not have clinical celiac disease (your blood test for celiac disease comes out negative) but you still show the symptoms of gluten sensitivity. This condition is being variously described as the notorious placebo effect in some places and nocebo effect in most others. The term placebo effect to describe this condition is entirely wrong, placebo effect occurs when a medically inert substance (placebo) causes perceived or actual health improvements in the patient taking the placebo. A nocebo effect on the other hand occurs when a harmless substance causes harm through psychological or physiological routes. At least one group of researchers have attributed the gluten related symptoms of individuals that do not have celiac disease or whose blood tests come out negative for celiac disease to the nocebo effect.

To assume that the discomfort and pain that non-celiac gluten sensitive individuals go through is imaginary or “is just in their heads” would be akin to making a mistake that every judge avoids to make in the court of law. A judge/justice system will go a long way to insure that a guilty person is not set free (sending innocent person to jail is considered more deplorable). In statistical and clinical term this is called as committing a type 2 error; failing to reject a false null hypothesis. In statistical and clinical studies committing a type 2 error is considered more deplorable than committing a type 1 error (sending an innocent person to jail). All statisticians and clinicians are taught about the severity of committing a type 2 error and are encouraged to reduce the probability of committing type 2 error. Even if gluten is found “not-guilty” in non-celiac gluten sensitivity, one does not have the grounds to absolve gluten in aiding and abetting celiac disease. Celiac disease is real, and is caused by gluten in genetically predisposed individuals.

So whats the big fuss about?

Gluten intolerance, celiac disease, and gluten free diet are no doubt reaching fad-level status. I am not using the word “fad” in a pejorative sense here. We have gluten-free aisles in grocery stores, gluten-free menu options, gluten free bread andgluten free dog food. It is no surprise that this fad is being exploited by the market. Consumers created the market, and the market is creating new products for new consumers (dogs), the whole process is snowballing akin to a culturalrunaway selection process. This has also created a anti-gluten social-psychology. There is no doubt that eating gluten free diet has become “cool”, hating on those who eat a gluten-free diet is also fast become a fad. Shaming gluten free eaters is an actualthing. Throw in the nocebo effect in this anti-gluten free diet socio-psychological milieu, and it gives the haters and the shamers something scientific and legible sounding to latch onto, thereby giving their hating and shaming more credibility. I gave this background to give my perspective on why I think the gluten-sensitivity-doesn’t-exist caught on in the media and the internet.

How did the whole gluten-sensitivity-doesn’t-exist thing begin?

Well to answer this question you have to first ask the question “How did the whole gluten-sensitivity exists thing begin?”

In 2011, Biesiekierski et. al. published the results of a double-blind randomized controlled trial. A double-blind randomized controlled trial is considered as the gold standard for clinical trials. Group of individuals were randomly assigned to either the gluten group or the placebo group. Gluten was administered in the form of two bread slices plus one muffin every day for a period of 6 weeks. The researchers found that the participants that were assigned to the gluten group were significantly worse within 1 week of gluten administration, they reported bloating, pain and tiredness significantly more than the placebo group. Two important things. Firstly, the participants were blind to consumption of gluten or placebo. Secondly, the subjects that were recruited to the study were non-celiac diseases patients who reported symptoms of irritable bowel syndrome. Although the authors never found or proposed an exact biological mechanism linking gluten to the symptoms, the results of the study led many doctors and laymen to adopt a gluten free diet in hopes of alleviating their general health and well being.

Since no biological mechanism was found the authors of the study created anamazingly rigorous experimental design to determine whether gluten was guilty in non celiac gluten sensitivity. This study was also a double blind randomized controlled trial, where all food intake was controlled, gluten was added and removed from the diet in different experimental arms and fecal and urine samples were taken throughout the study. All participants were put on a run-in period of a 2 weeks on a gluten free, low-FODMAP diet. After the run-in period the participants were randomized one of the three arms of the study: high gluten (16 grams/day), low gluten (2 grams/day and 14 grams/day of whey) and control-no gluten (16 grams/day of whey) in two back to back trials; 7-day and 3-day. They authors used abdominal symptoms like bloating, wind, satisfaction with stool consistency, abdominal pain, tiredness and nausea to asses the effect of gluten. They also took feces, urine and blood samples to asses bio-medical markers to check for immune reactions to gluten.

What did the authors find? All experimental arms of the study, high gluten, low gluten and placebo, showed a general worsening of abdominal symptoms, even though the biomedical markers showed no change. How could this be? The authors attribute this to the nocebo effect. Nocebo effect occurs when a harmless substance creates a harmful effect. The patients might have assumed that they were ingesting something harmful (gluten?) and this might have resulted in a perceived worsening of symptoms, the symptoms reported were tiredness, nausea, bloating, gas, and a constipation. The authors propose one explanation for the nocebo effect “..that frequent visits to clinic for blood taking, fecal collection, wearing accelerometers, and completion of daily questionnaires, all while following a restrictive diet. This might have been perceived as stressful and might have contributed to the nocebo effect and, therefore, positive symptomatic responses across all treatment arms”. The frequent visits to the hospital could have instilled a general belief in all the patients across different treatment arms that they are generally sick. Going to the clinic can have real adverse psychological and physiological effects on patients. In blood pressure science this effect is know as the “white coat syndrome”. White coat syndrome is a phenomenon in which patients exhibit higher blood pressure in a clinical setting as compared to other settings, it is most likely caused by the anxiety created by the visit to the clinic. So in this study the nocebo was probably not gluten, but the frequent clinic visits.

Finally, the authors also conclude that whey protein, that was given to the control group and the low gluten group itself might have triggered symptoms in same patients during the study. This is critical because there were three treatment arms and all of them showed a general worsening of symptoms, could it be that the gluten arm showed a general worsening because of gluten, and the low gluten arm (2 gms/day of gluten and 14 gms/day of whey) and the control arm (16 grams/day of whey) showed a general worsening of symptoms because of whey? The authors acknowledge this in their paper by noting that “the results from the 7-day trial suggested that whey protein itself might have triggered symptoms in some patients. However, the effects of whey protein independent of gluten were not reproduced in the 3-day rechallenge.”

Another important finding of this study was the effect of FODMAPs on the abdominal symptoms. FODMAPs are short chain carbohydrates that are poorly absorbed in the intestine thereby causing discomfort in the stomach. The subjects in the study were put on a low-FODMAP diet during the run-in period. This was done as abdomincal symptoms due to FODMAP could confound the symptoms due to gluten. It was found that low-FODMAP diet improved abdominal symptoms during the run-in period as compared to the baseline (before study).

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“No Effects of Gluten in Patients With Self-Reported Non-Celiac Gluten Sensitivity After Dietary Reduction of Fermentable, Poorly Absorbed,Short-Chain Carbohydrates”



A nocebo effect during the 7 and 3 day trial and improvements of symptoms during the run-in period led the authors to conclude that gluten may cause abdominal symptoms only in the presence of FODMAPs. Many gluten containing cereals are also high in FODMAPs. A gluten-free diet tends to also reduce the intake of FODMAPs and therefore the improvement in abdominal symptoms may be due to reduction in FODMAPs and not gluten in this study population of IBS individuals.

The authors raise an intriguing possibility of gluten and FODMAPs having separate effects on mental health and gut respectively. Gluten is also known to haveneurological effects and possibly cause anxiety and depression. It is very likely then that gluten free diet leads to improvement in well being through the improvement of mental health. A less depressed and anxious person is expected to make better food choices than a depressed and anxious person. Gluten is still the mediator of health, not in the gut, but in the brain.

If FODMAPs is found as the real culprit, does this mean that wheat can be let of the hook? Short answer: no. As wheat is a major source of fructan; a type of FODMAP. In such a case wheat intolerance instead of gluten intolerance becomes a proper description of this condition. Researchers are proposing that non-celiac wheat sensitivity is a better label than non-celiac gluten sensitivity.

In conclusion, there are some methodological problems with the FODMAPs study. Whey, the white coat syndrome and the nocebo (gluten) effect could have equally contributed to the general worsening of symptoms in all treatment arms. Even with these problems the authors should be credited for the rigorous study they conducted. Like true scientists they tried to minimize some very crucial confounders. Having said that, one doesn’t form generalized public health guidelines based on one study. Both these studies gained massive media attention for reasons cited above. FODMAPs and gastrointestinal diseases haven’t received much research attention in the past, hopefully this study will change that. The FODMAP’s study questions the existence of non-celiac gluten sensitivity since it was found that FODMAPs was the real mediator of abdominal symptoms. However, it is also possible that non-celiac gluten sensitivity is a real entity and is confounded by a low-FODMAPs diet. There are important questions to be asked and answered and only large scale and long term clinical trials can get us closer to understanding gluten intolerance.

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