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Fructans Suspect in Non-Celiac Gluten Sensitivity
      03/19/18 02:44 PM

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Gastroenterology > General Gastroenterology

Fructans Suspect in Non-Celiac Gluten Sensitivity

Randomized double-blind trial casts doubt on need for gluten-free diets in NCGS

by Diana Swift, Contributing Writer
March 08, 2018

Note that this small study found that fructans, not gluten, promote the worst symptoms in patients with self-reported non-celiac gluten sensitivity.

Be aware that the effect of placebo is very strong in studies of this type, potentially adding noise to the outcome data that make these estimates less reliable.

A Norwegian study has found that fructan is somewhat more likely than gluten to induce the symptoms of non-celiac related gluten sensitivity (NCGS), a term first used in 1978.

In a randomized, double-blind crossover trial of 59 patients with self-reported intolerance to wheat, rye, and barley, but no celiac disease, the overall symptom score was highest after challenge with the carbohydrate fructan. Fructan is a member of the fermentable oligo-di-monosaccharides and polyols (FODMAPs) family, and is often found in gluten-containing foods such as wheat.

The study, published in Gastroenterology and led by Gry I. Skodje, MSc, RD, a PhD student at Oslo University Hospital, found that gluten challenge had no effect at the overall group level and triggered the highest level of symptomatic response in just 13 of the 59 participants.

Skodje and colleagues pointed out that NCGS symptoms often improve after gluten withdrawal even though no celiac disease is present, and that gastrointestinal symptoms often improve on low-FODMAP diets. Currently the mechanisms of NCGS remain unclear; the disorder has no known biomarkers.

The study was conducted at the hospital during 2014-2016; the patients with self-reported NCGS, were mostly female (n=53), and had a mean age of approximately 44. Participants were randomized to the following dietary arms based on a 7-day challenge with different muesli bars: gluten 5.7 g, fructan 2.1 g, and placebo -- all in the roughly 400-kcalorie range. After a 7-day washout period, participants crossed over into a different group until they had completed all three challenges; the reported compliance was high.

Symptoms were measured using the Gastrointestinal Symptom Rating Scale-Irritable Bowel Syndrome (GSRS-IBS). Overall scores differed moderately across the gluten, fructan, and placebo challenges, with mean respective values of 33.1±13.3, 38.6±12.3, and 34.3±13.9 (P=0.04).

The mean scores for bloating specifically were 9.3±3.5, 11.6±3.5, and 10.1±3.7, respectively (P=0.004). The overall score for participants consuming fructan was higher than for those consuming gluten (P=0.049), as was the GSRS bloating score (P=0.003). Just 13 participants had the highest overall GSRS-IBS score after consuming gluten, 24 had the highest score after consuming fructan, and, interestingly, 22 had the highest score after consuming placebo -- due perhaps, the researchers said, to the nocebo effect of anticipating negative outcomes after any intervention, which has been as high as 40% in other research.

"The large placebo response, as seen in previous studies, demonstrates how difficult it is to correctly identify which patients should be gluten-free."

The authors pointed out that the respective muesli bars were carefully formulated to contain no other potential triggers, and when pretested on biopsy-tested celiac patients, the gluten bars induced a strong duodenal immune response.

In secondary findings, the fructan effect was not restricted to abdominal symptoms, the team found. The Short Form (36) Health Survey vitality scale was significantly lower, and the Visual Analog Scale weakness significantly increased in response to fructan compared with to gluten and placebo: mean 44.3, 38.2, and 44.4, respectively (P=04). Using the Giessen Subjective Complaint List, the highest weakness was found after the fructan challenge versus gluten and placebo: 32.8, 42.5, and 33.5, respectively (P=0.02).

"The findings weaken the role of gluten as a symptom inducer in patients with self-reported NCGS," Skodje and colleagues wrote." They pointed to Australian research showing that NCGS patients placed on a low-FODMAP diet with tight control of background confounders had no response to rechallenge with gluten.

Javier Molian-Infante MD, of Hospital San Pedro de Alcantara in Caceres, Spain, who was not involved with the study, commented that other research has found that gluten plays only a minor role in self-diagnosed NCGS sensitivity.

"The term would be better changed to 'wheat and/or cereal sensitivity,'" Molina-Infante told MedPage Today. "Aside from gluten, a protein, fructans, which are carbohydrates, [other protein] components are under suspicion as symptom triggers in non-celiac, non-wheat sensitivity."

Writing in an accompanying editorial, Kristin Verbeke, PhD, Pharm, of the University of Leuven in Brussels, Belgium, noted that current research is homing in other problematic components. One is α−amylase/trypsin inhibitors (ATIs), pest-proofing proteins that are potent promoters of inflammation through activation of the innate immune system, including dendritic cells, monocytes, and macrophages via stimulation of the toll-like receptors. The need for ever-greater crop yields and greater pest resistance has led to the development of wheat cultivars higher in ATIs, she explained.

In addition, Verbeke continued, while fructans and other FODMAPs likely contribute to NCGS, they may only explain the gastrointestinal symptoms and not the disorder's extraintestinal symptoms such as neurologic dysfunction, psychological disturbances, fibromyalgia, and skin rash -- "Therefore, it is unlikely that they are the sole cause of NCGS."

Studies such as Skodje et al's disentangle the contribution of different suspect components in cereal grains and are very much needed, Verbeke said. "They might stimulate the food industry to develop adapted food products, eliminating the need for gluten-free diets for NCGS patients." And that would be desirable since a gluten-free diet tends to reduce consumption of whole grains and cereal fiber and whole grains, potentially raising cardiovascular risk, she said.

Study limitations, the team said, included a relatively small sample, the heterogeneity of NCGS populations, the potential for recall bias during recording of symptoms, and the possibility of unreported dietary changes during the course of the study.

This study was funded by the Extra Foundation Health and Rehabilitation, the Norwegian Celiac Association, the Throne Holst Foundation for Nutrition Research, and the Wedel Jarlsberg Foundation.

One of the co-authors has published an information/recipe book on the low-FODMAP diet, and his institution receives royalties from the sale of The Monash University Low-FODMAP Diet App. Skodje and the other authors reported having no competing interests.

Neither Molian-Infante nor Verbeke reported having any conflicts of interest in regard to their comments.

Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine

last updated 03.08.2018

Primary Source
Source Reference: Skodje GI, et al "Fructan, Rather Than Gluten, Induces Symptoms in Patients with Self-Reported Non-Celiac Gluten Sensitivity" Gastroenterology 2018; 154(3): 529–539.
Secondary Source
Source Reference: Verbeke K "Non-Celiac Gluten Sensitivty: What is the Culprit?" Gastroenterology 2018; 154(3): 471–473.

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