A new study suggests that for many patients with irritable bowel syndrome who believe wheat or gluten trigger their symptoms, the expectation of a food causing discomfort may play a larger role than the food itself. Research published in The Lancet Gastroenterology & Hepatology found no significant difference in symptom flare-ups when these patients consumed bars containing wheat, purified gluten, or a gluten-free sham substance.
Researchers launched the study to address a persistent puzzle in the management of irritable bowel syndrome. While many patients report that their digestive symptoms improve on a gluten-free diet, it has remained unclear if wheat or gluten are the direct biological triggers. The scientific rationale for this investigation is rooted in the powerful connection between the gut and the brain, which allows a person’s expectations to create real, physical symptoms.
This mind-body connection can work in two opposing ways. When a person’s positive belief in a treatment leads to genuine symptom improvement, even if the treatment is inactive, it is known as the placebo response. Conversely, when a person’s negative belief or fear about a substance causes them to experience adverse effects from it, even if the substance is harmless, it is called the nocebo response.
Because these effects are known to be especially strong in conditions like irritable bowel syndrome, it is difficult to separate a true food reaction from a psychologically driven one. To untangle these factors, a research team led by Caroline Larissa Seiler at McMaster University designed this study to scientifically isolate the physical impact of wheat and gluten from the powerful influence of patient beliefs.
The investigation was a randomized, double-blind, sham-controlled crossover trial. This design means that each participant served as their own control, trying all three interventions at different times. It also means that neither the participants nor the researchers interacting with them knew which intervention was being administered at any given time, which helps prevent bias. The team recruited adults diagnosed with irritable bowel syndrome who had previously reported feeling better after following a gluten-free diet. Twenty-eight participants completed the full study.
Each participant went through three distinct seven-day challenge periods, separated by two-week washout periods where they maintained their gluten-free diet. During each challenge week, participants ate one specially prepared cereal bar per day. There were three types of bars, all designed to look, taste, and smell identical.
One bar contained whole wheat flour, which includes both gluten and other wheat proteins like amylase trypsin inhibitors. The second bar contained purified gluten with most other wheat proteins removed. The third bar was a sham, made from gluten-free and wheat-free flour.
Participants were randomly assigned to a sequence for consuming the three types of bars. The primary measurement was whether a participant’s symptoms worsened by at least 50 points on a standard scale known as the Irritable Bowel Syndrome Symptom Severity Score.
The study’s main finding was that there were no statistically significant differences in symptom worsening among the three challenges. After the wheat challenge, 39 percent of participants experienced a significant worsening of symptoms. Following the gluten challenge, 36 percent reported a symptom flare-up.
After the sham challenge, which contained neither wheat nor gluten, 29 percent of participants still experienced a significant worsening of symptoms. The small differences between these groups were not large enough to be considered statistically meaningful, suggesting that wheat and gluten were not the specific triggers for the majority of these individuals.
Adverse events were common, but they occurred at nearly identical rates across all three conditions. An overwhelming 93 percent of participants reported adverse events like bloating, abdominal pain, or changes in bowel habits after each of the wheat, gluten, and sham challenges. The fact that negative symptoms were reported just as frequently after consuming the inactive sham bar points toward a powerful nocebo effect, where the anticipation of symptoms appeared to generate them.
A secondary and revealing component of the study involved objectively measuring adherence to the diet protocol. Participants were asked to provide stool samples, which were tested for gluten immunogenic peptides, a reliable marker of recent gluten consumption. While participants self-reported high levels of compliance, with 97 percent of the challenge bars reportedly consumed, the objective stool tests told a different story.
The results showed that 57 percent of patients had detectable gluten in their stool at times when they should have been on a strict gluten-free diet, such as before a challenge week or during the sham week. Conversely, 25 percent of patients had no detectable gluten after the wheat or gluten challenges, suggesting they did not consume all the challenge bars. Ultimately, the objective data indicated that only about one-third of the participants were fully compliant with the study protocol.
The researchers also conducted a follow-up to assess how learning their personal results affected patients’ beliefs and behaviors. After the trial, each participant was informed about their individual responses to the wheat, gluten, and sham bars. Despite this personalized feedback, most participants did not change their dietary habits. Of the 26 patients who received their results, 17 continued to follow a gluten-free diet.
The decision to continue the diet was mostly driven by a persistent belief that it improved their symptoms and quality of life. Even among individuals who were shown that their symptoms flared up in response to the sham bar, or that they had no reaction to gluten, most maintained their gluten-free lifestyle. This finding highlights how deeply entrenched beliefs about food triggers can be, resisting even direct, personal scientific evidence to the contrary.
The study did have some limitations. The number of participants was small, and recruitment was impacted by the COVID-19 pandemic, which also caused some data from blood tests and imaging to be incomplete. The study population was also not very diverse, consisting mostly of white women, which means the findings may not be generalizable to all people with irritable bowel syndrome. Additionally, the amount of wheat used in the challenge bar was relatively low to avoid confounding effects from other components in wheat, so it is possible that higher doses could trigger symptoms in some individuals.
Looking forward, the research carries important implications. The findings suggest that for a significant portion of irritable bowel syndrome patients with self-perceived gluten sensitivity, it is the belief about gluten, not gluten itself, that may be driving symptoms. The study powerfully demonstrates the unreliability of self-reported dietary adherence and makes a strong case for including objective markers, like stool analysis, in future nutrition trials.
The results also suggest that helping patients effectively manage their condition may require more than just dietary advice. Psychological support aimed at helping patients re-evaluate their beliefs about food triggers and safely reintroduce foods into their diet could be an important component of care.
The study, “Effect of gluten and wheat on symptoms and behaviours in adults with irritable bowel syndrome: a single-centre, randomised, double-blind, sham-controlled crossover trial,” was authored by Caroline Larissa Seiler, Gaston Horacio Rueda, Pedro Miguel Miranda, Andrea Nardelli, Rajka Borojevic, Amber Hann, Sara Rahmani, Russell De Souza, Alberto Caminero, Valentina Curella, Manjusha Neerukonda, Stephen Vanner, Detlef Schuppan, Paul Moayyedi, Stephen Michael Collins, Elena Francisca Verdu, Maria Ines Pinto-Sanchez, and Premysl Bercik.
