Gastrointestinal symptoms of gluten sensitivity in people without coeliac disease are a nocebo effect driven by negative expectations, study findings suggest.
A prospective blinded trial of gluten and placebo ingestion in participants with non-coeliac gluten sensitivity found that gastrointestinal symptoms were experienced more frequently by those who had high expectations of symptoms.
Conducted by research teams at the universities of Maastricht and Leeds, the study provides further evidence of an interaction at the gut-brain axis among people who avoid gluten despite not having a diagnosis of coeliac disease or wheat allergy, according to the authors.
In their trial, 83 adults who self-reported gastrointestinal symptoms within eight of gluten consumption but without coeliac disease and wheat allergy were recruited.
Participants were randomly assigned to one of four groups based on the expectation to consume gluten-containing or gluten-free oat bread for breakfast and lunch and actual intake of gluten-containing or gluten-free oat bread.
All participants and investigators were masked to the actual gluten assignment, and participants were also masked to the expectancy part of the study.
The primary outcome was overall score (VAS) for gastrointestinal symptoms, abdominal discomfort, and bloating, which was measured before breakfast)and hourly until four hours after lunch.
The results, published in The Lancet Gastroenterology and Hepatology, showed that participants who were told they would consume gluten and subsequently received gluten-containing oat bread had significantly higher mean overall GI symptom scores than those who consumed gluten but were not expecting it (16·6 vs 6·9 mm, difference 9·6 mm [95% CI 3·0 to 16·2], p=0·0010).
Participants who expected gluten but received gluten-free placebo had GI scores of 11·7 mm, while those who had no expectation of gluten but received gluten had GI symptom scores of 6.9mm. Those who had neither expectation nor ingestion of gluten had GI scores of 6.9mm.
The study investigators concluded that GI symptoms were driven more by expectation while gluten intake did not have a significant influence on overall gastrointestinal symptoms within each expectancy group.
“Although an additional effect of gluten could not be ruled out, our findings indicate that the nocebo effect has an important role in symptom occurrence in people with non-coeliac gluten sensitivity,” they wrote.
However they stressed that although the cause was partly “in the mind”, this did not mean that the symptoms were not real.
“Due to the influence of [gut–brain] interactions … people can genuinely experience symptoms such as stomach ache, bloating or diarrhoea after eating gluten,” said investigator Professor Daisy Jonkers, of the Department of Gastroenterology-Hepatology at Maastricht University. “But the cause of these complaints is not only eating gluten, so a gluten-free diet isn’t the only solution.”
To treat this problem, the researchers want to conduct further studies on the influence of the brain on the development of bowel complaints.
“For example, we’d like to know exactly which areas in the brain are involved,” said Professor Jonkers, “and we also want to find out what substances play a role in the communication between the brain and the gut, and whether people might respond differently to them.”
“It’s also quite possible that some people can’t tolerate wheat products because of substances in wheat other than gluten, and that there is indeed something in wheat that can lead to overstimulation of the immune system, for example, or excessive production of gas by the gut flora. This is also something we’d like to investigate.”
An accompanying commentary said the study “provided further evidence to support the idea that non-coeliac gluten sensitivity is not a distinct clinical entity but an umbrella term encompassing a heterogeneous group of patients, with a substantial symptom overlap with coeliac disease, IBS, functional dyspepsia, and food allergy or sensitivity.”
“Hence, the diagnosis and management of patients with self-reported non-coeliac gluten sensitivity requires a comprehensive and individualised approach to improve patient outcomes and to avoid the potential harms of an unnecessary long-term gluten-free diet,” the authors concluded.