In 2011, Peter Gibson, a professor of gastroenterology at Monash University and director of the GI Unit at The Alfred Hospital in Melbourne, Australia, published a study that found gluten, a protein found in grains like wheat, rye, and barley, to cause gastrointestinal distress in patients without celiac disease, an autoimmune disorder unequivocally triggered by gluten. Double-blinded, randomized, and placebo-controlled, the experiment was one of the strongest pieces of evidence to date that non-celiac gluten sensitivity (NCGS), more commonly known as gluten intolerance, is a genuine condition.

By extension, the study also lent credibility to the meteoric rise of the gluten-free diet. Surveys now show that 30% of Americans would like to eat less gluten, and sales of gluten-free products are estimated to hit $15 billion by 2016 -- that's a 50% jump over 2013's numbers!

But like any meticulous scientist, Gibson wasn't satisfied with his first study. His research turned up no clues to what actually might be causing subjects' adverse reactions to gluten. Moreover, there were many more variables to control! What if some hidden confounder was mucking up the results? He resolved to repeat the trial with a level of rigor lacking in most nutritional research. Subjects would be provided with every single meal for the duration of the trial. Any and all potential dietary triggers for gastrointestinal symptoms would be removed, including lactose (from milk products), certain preservatives like benzoates, propionate, sulfites, and nitrites, and fermentable, poorly absorbed short-chain carbohydrates, also known as FODMAPs. And last, but not least, nine days worth of urine and fecal matter would be collected. With this new study, Gibson wasn't messing around.

37 subjects took part, all confirmed not to have celiac disease but whose gastrointestinal symptoms improved on a gluten-free diet, thus fulfilling the diagnostic criteria for non-celiac gluten sensitivity.** They were first fed a diet low in FODMAPs for two weeks (baseline), then were given one of three diets for a week with either 16 grams per day of added gluten (high-gluten), 2 grams of gluten and 14 grams of whey protein isolate (low-gluten), or 16 grams of whey protein isolate (placebo). Each subject shuffled through every single diet so that they could serve as their own controls, and none ever knew what specific diet he or she was eating. After the main experiment, a second was conducted to ensure that the whey protein placebo was suitable. In this one, 22 of the original subjects shuffled through three different diets -- 16 grams of added gluten, 16 grams of added whey protein isolate, or the baseline diet -- for three days each.

Analyzing the data, Gibson found that each treatment diet, whether it included gluten or not, prompted subjects to report a worsening of gastrointestinal symptoms to similar degrees. Reported pain, bloating, nausea, and gas all increased over the baseline low-FODMAP diet. Even in the second experiment, when the placebo diet was identical to the baseline diet, subjects reported a worsening of symptoms! The data clearly indicated that a nocebo effect, the same reaction that prompts some people to get sick from wind turbines and wireless internet, was at work here. Patients reported gastrointestinal distress without any apparent physical cause. Gluten wasn't the culprit; the cause was likely psychological. Participants expected the diets to make them sick, and so they did. The finding led Gibson to the opposite conclusion of his 2011 research:

“In contrast to our first study… we could find absolutely no specific response to gluten."

Instead, as RCS reported last week, FODMAPS are a far more likely cause of the gastrointestinal problems attributed to gluten intolerance. Jessica Biesiekierski, a gastroenterologist formerly at Monash University and now based out of the Translational Research Center for Gastrointestinal Disorders at the University of Leuven in Belgium,* and lead author of the study alongside Gibson, noted that when participants consumed the baseline low-FODMAP diet, almost all reported that their symptoms improved!

"Reduction of FODMAPs in their diets uniformly reduced gastrointestinal symptoms and fatigue in the run-in period, after which they were minimally symptomatic."

Coincidentally, some of the largest dietary sources of FODMAPs -- specifically bread products -- are removed when adopting a gluten-free diet, which could explain why the millions of people worldwide who swear by gluten-free diets feel better after going gluten-free.

Indeed, the rise in non-celiac gluten sensitivity seems predominantly driven by consumers and commercial interests, not quality scientific research.

"On current evidence the existence of the entity of NCGS remains unsubstantiated," Biesiekierski noted in a review published in December to the journal Current Allergy and Asthma Reports.

Consider this: no underlying cause for gluten intolerance has yet been discovered. Moreover, there are a host of triggers for gastrointestinal distress, many of which were not controlled for in previous studies. Generally, non-celiac gluten sensitivity is assumed to be the culprit when celiac disease is ruled out. But that is a "trap," Biesiekierski says, one which could potentially lead to confirmation bias, thus blinding researchers, doctors, and patients to other possibilities.

Biesiekierski recognizes that gluten may very well be the stomach irritant we've been looking for. "There is definitely something going on," she told RCS, "but true NCGS may only affect a very small number of people and may affect more extraintestinal symptoms than first thought. This will only be confirmed with an understanding of its mechanism."

Currently, Biesiekierski is focused on maintaining an open mind and refining her experimental methods to determine whether or not non-celiac gluten sensitivity truly exists.

"We need to make sure that this research is as well controlled as possible and is reproducible," Biesiekierski told RCS, subsequently adding the quintessential adage of proper science.

"Much, much more research is needed."

Source: Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR. "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 Aug;145(2):320-8.e1-3. doi: 10.1053/j.gastro.2013.04.051. Epub 2013 May 4.

Source: Biesiekierski JR, Muir JG, Gibson PR. "Is gluten a cause of gastrointestinal symptoms in people without celiac disease?" Curr Allergy Asthma Rep. 2013 Dec;13(6):631-8. doi: 10.1007/s11882-013-0386-4.

*Section updated 5/15 to reflect Dr. Biesiekierski's new position.

**Section updated 5/16 to clarify that all of the subjects fulfilled the diagnostic criteria for NCGS.