NCGS – More Than Gluten To Blame?

The debate about whether or not non-celiac gluten sensitivity (NCGS) is a real entity continues. Research has been done purporting to both prove and disprove the condition. A study that attracted a lot of attention was done by one of the teams that originally found some evidence that NCGS might be real. This team wanted to reproduce and expand on some of their research. They were surprised to discover that gluten did not seem to be the cause of the symptoms in their subsequent study of patients with NCGS.

The researchers are from Australia. They published a study in 2011about the reactions of 34 people with NCGS to gluten. These patients had been on a gluten-free diet and were not experiencing a lot of symptoms. A randomized, double-blind, placebo-controlled protocol was followed. Half of the participants got a gluten-containing diet and half did not for a period of up to six weeks. At the end of the study, their symptoms were compared using a self-reporting tool called the visual analog scale (VAS). This mainly asks about intestinal symptoms. In addition, they were tested for any evidence of inflammation in blood or stool.

Within one week, the participants who were getting gluten (compared with those that did not) had statistically significant increases in reported symptoms, including fatigue, pain, bloating, disatisfaction with the consistency of their stool, and total symptoms. However, in this study, there were no changes in any blood or stool tests in the group who got gluten. They made no antigliadin antibodies.

The researchers concluded, “‘Non-celiac gluten intolerance’ may exist, but no clues to the mechanism were elucidated.” Nevertheless, this study seemed to show that NCGS might be a real condition, even though few people were actually studied.

The research group undertook another study. This research was designed to evaluate the response to different amounts of gluten, while minimizing exposure to other foods that may be difficult to digest. Research subjects with NCGS well controlled on a gluten-free diet were split into three groups. Using a computer to randomly assign order, each group got one of three diets, with differing amounts of gluten. The main goal was to look at the changes in symptoms measured by the same scale (the VAS) used in their first study.

A major difference in the more recent study was that before subjects got the test diets, they had what is called a “run-in period” during which certain other poorly-digestible foods were removed from their diet. The researchers hoped this would make the responses to the gluten-containing foods even more clear. They were also looking to see how reproducible the effects of gluten were, by giving people different diets in different order. For part of the study they looked at blood for evidence of inflammation, antibodies to whole and deamidated gliadins and any other evidence of actual celiac disease or wheat allergy. They also looked at stool specimens.

The results surprised the investigators, because they found no reproducible symptoms when the participants consumed the gluten-containing diets

The most important information that emerged from this study may have been that people with NCGS may be reacting to something in wheat besides gluten and gliadins. Wheat contains fructans. Fructans are FODMAPS, which stands for fermentable, poorly absorbed, short-chain carbohydrates or fermentable, oligo-, di-, monosaccharides, and polyols. These substances are known to be hard to absorb and to cause many of the same symptoms as NCGS and irritable bowel syndrome. FODMAPS were removed from the diets of all the participants before they started the test food.

There were two parts to this study. 37 subjects with suspected NCGS and irritable bowel syndrome symptoms participated in the first part. They recorded their usual diet (gluten free) and symptoms for a week. They started with the run-in period of two weeks with a diet free of gluten and FODMAPs.

They were then randomly assigned by computer to one of the three test arms, a high-gluten diet, a low-gluten diet (not gluten free) and a diet with no gluten but with added whey protein, considered placebo. All the food was prepared so that differences in taste or texture could not be appreciated. After a week eating one of the diets, each participant had a washout period of at least two weeks back on the gluten-free, low-FODMAP diet, until any symptoms resolved. They then crossed over to a randomly assigned second diet. This was repeated until each person had eaten each of the three diets. Anyone with intolerable symptoms was allowed to stop that particular diet and eat the baseline diet until their symptoms resolved. They then went on to the next diet.

Symptoms were recorded, diets were recorded, and tests were done on stool and blood. The VAS was used to measure symptoms as was another scale measuring fatigue.

The study subjects did not react specifically to gluten in the diet. Essentially all of the participants recorded significantly improved symptoms during the low FODMAP run in as compared with their usual state of health. They then experienced the most symptoms during the first trial diet, no matter which one. Their symptoms were less pronounced during the second and third trial diets. Order mattered. Gluten content did not. Only two patients had to stop a trial diet early; one was eating high gluten and the other the placebo diet.

There were no statistically significant changes in any blood or stool tests during the first half. Participants did not make IgA or IgG antibodies to gliadin or deamidated gliadin, some of which have been found in patients with NCGS in other studies.

Results from this first part of the study were used to help design the second part, which was shorter, a three-day challenge. 22 of the original participants continued on. The baseline diet had even more potential intestinal irritants removed, such as dairy products and chemical additives. Symptoms were recorded, but not blood and stool tests.

There were three treatment diets, all with the low irritant level, one with high gluten levels, one with high amounts of whey protein (from milk) and one was a placebo diet. Washout periods between diets were at least three days. Each subject got all three diets in different orders. Changes in symptoms were similar in all three treatment groups. The first study diet caused the most symptoms.

Reactions to the gluten-containing diets in the two parts of the study were compared for all the subjects who took part in both. The reactions were not consistent. For example, two participants who reacted to the high-gluten diet in the first part of the study did not in the second. There were also two who reacted to gluten in the second part, but they did not in the first part. Statistically speaking, there was no correlation between the results of the two parts of the study in terms of reaction to gluten.

In both parts, it was the order of the diet that could predict the strength of the reactions. Participants had the most symptoms on whichever diet they got first in both halves of the study.

The researchers were surprised at the results, which did not agree with their research published in 2011. They said, “Generally, NCGS is viewed as a defined illness, much like celiac disease, where gluten is the cause and trigger for symptoms. In such a case, it would be anticipated that removal of gluten from the diet would lead to minimal symptoms and subsequent exposure to gluten would lead to specific triggering of symptoms. The results of the current study have not supported this concept.”

Since participants had improvement of their symptoms during the run-in, low-FODMAP (and gluten-free) diet, they suggested that some or many people with NCGS may in fact be reacting to fructans instead of gluten.

There were participants who had the run –in diet followed by placebo, during which their symptoms increased, followed by a low-gluten and a high-gluten diet which did not significantly increase their symptoms. This speaks against gluten as causing symptoms in this specific group of people.

Researchers also noted that lowering all of the possible intestinal irritants might make some people with this condition less likely to react to gluten, because of a decrease in what could be called “background noise.”

They discussed possible reasons for results, including possible flaws in the study, but stand by their findings. They said, “In conclusion, these consecutive double-blind, randomized, placebo-controlled, cross-over rechallenge studies showed no evidence of specific or dose-dependent effects of gluten in patients with NCGS placed on a low FODMAP diet.”

It remains to see if other researchers can reach the same conclusions with larger groups, and also to see how important the presence of FODMAPS might be in terms of symptoms.

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References
Biesiekierski JR, Peters SL, Newnham ED, et al. No Effects of Gluten in Patients With Self-Reported Non-Celiac Gluten Sensitivity After Dietary Reduction of Fermentable, Poorly Absorbed,Short-Chain Carbohydrates. Gastroenterology 2013;145:320–328.
Biesiekierski JR, Newnham ED, Irving PM, et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. American Journal of Gastroenterology 2011;106:508–514.