Non-Celiac Wheat Sensitivity: The Role of Expectation in Symptom Development

Understanding NCWS

NCWS is characterized by symptoms similar to Celiac Disease (CD) or Wheat Allergy (WA), such as abdominal pain, fatigue, headaches, skin rashes, and mental confusion (1). NCWS is diagnosed after excluding CD and WA, and symptoms typically improve on a gluten-free diet. However, the cause of NCWS onset remains a subject of ongoing research. 

Understanding of the underlying mechanisms behind the role of gluten or additional wheat components in NCWS is also poor. These other molecules in wheat that may contribute to symptoms include amylase trypsin inhibitors (ATIs) or fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs), such as fructans. The immune system, intestinal inflammation, gut dysbiosis, altered intestinal barrier function and/or psychological factors may all play a role (2,3). 

The prevalence of NCWS varies, with estimates ranging from 0.6% to 13% globally. The prevalence is particularly high among those with Irritable Bowel Syndrome (IBS), where the rate may be up to 46.1% (4). Wheat is also among the top five foods reported to trigger IBS symptoms (5). In this new study, 35% of participants met the Rome IV criteria for IBS (6).

The Nocebo Effect in NCWS

The nocebo effect describes when negative expectations lead to symptom manifestation. Among those with NCWS, expectation of symptoms related to gluten can influence perceived intolerances, which also often then leads to restriction of gluten. 

Previous research on the nocebo effect and the role of expectations in mediating symptoms has found that up to 41% of participants with suspected NCWS show similar or increased symptoms in response to placebo versus a gluten challenge (7). However, other studies have shown no effect (8,9,10).

This recent study by de Graaf et. al. provides insight into the nocebo response by exploring the relationship between expectancy versus actual gluten intake and its impact on symptoms. The findings help distinguish psychological factors from the physiological effects of gluten in NCWS and shed light on the involvement of the gut–brain interaction in influencing gastrointestinal sensory and motor function (11). 

Design and Methodology (6)

The randomized, double-blind, placebo-controlled study included 84 adults with self-reported NCWS who experienced gastrointestinal symptoms within 8 hours of gluten consumption and for whom CD and WA were excluded. Patients followed a gluten-free or gluten-restricted diet for at least one week before and throughout the study period and had to be asymptomatic or mildly symptomatic over that period. 

Participants were assigned to groups based on their expectation of consuming gluten-containing or gluten-free bread and their actual intake of these breads: 

• E+G+ (expectancy to consume gluten-containing bread and actual intake of gluten-containing bread)
• E+G– (expectancy to consume gluten-containing bread and actual intake of gluten-free bread)
• E–G+ (expectancy to consume gluten-free bread and actual intake of gluten-containing bread)
• E–G– (expectancy to consume gluten-free bread and actual intake of gluten-free bread)

The bread used for the trials consisted of a 100% gluten-free oat-based bread mix. The gluten-free bread was baked under gluten-free conditions and confirmed to be gluten-free by

the R5 RIDASCREEN Gliadin test. To make the gluten-containing bread, vital wheat gluten was added to the bread mix at 8.6% of the total dough weight, resulting in roughly 3.35 g of gluten per slice. For the 8 hours following the breakfast meal, participants completed an hourly questionnaire to assess symptoms. Participants received the same meals apart from the blinded differences in bread. All participants and researchers were masked to the group assignments and participants were also masked to the expectancy element of the study.

Research Findings (6)

Those in the E+G+ group (expecting and actually consuming gluten) reported significantly higher gastrointestinal symptom scores compared to the E–G+ group (not expecting and actually consuming gluten) (p=0.0010). Symptoms were also significantly higher for the E+G+ group compared to the  E–G– (not expecting and did not consume gluten) (p=0.0016). However, there was no difference between the E+G+ and the E+G– groups (expecting and did not consume gluten) (p=0.28), the E+G– and the E–G+ groups (p-0.47) or the E–G+ and E–G– (p=1.0).

Within each expectancy group, actual gluten intake did not significantly alter symptom scores, pointing towards the influence of expectancy in symptom development. Repeated exposure compounded differences in overall scores as well as some individual symptoms, with more pronounced differences after lunch compared to breakfast. Psychological and emotional factors, such as anxiety, depression, or somatisation, did not affect differences in overall and individual gastrointestinal symptoms during the study, which ran contrary to the researchers’ hypothesis. 

Still, due to the nature of the study design, concurrent effects of gluten cannot be excluded and continued research into biological mechanisms underlying gluten-related symptoms remains warranted.

Implications for Practice

The study highlights the relevance of a more nuanced approach in dietary counseling to address both the potential physiological effects of gluten and the psychological factors involved. Findings offer valuable insights into the management of NCWS and underline the importance of addressing both the psychological and physiological aspects of NCWS. 

It’s clear the nocebo effect plays a significant role in symptom development and warrants further research. Additional studies can seek to understand the role of the central nervous system (CNS) in mediating mechanisms behind the nocebo effect, which include expectancy and verbal suggestions. The gut–brain axis has multiple pathways, such as the autonomic and enteric nervous systems, the endocrine system, the hypothalamic–pituitary–adrenal axis, the immune system, and the gut microbiota and its metabolites. These all play a role in the bidirectional communication between the gastrointestinal tract and the CNS, which in turn may influence the nocebo response (6).

While research continues and in the meantime, consider the potential role of the nocebo effect in patients reporting NCWS. Management of food intolerances like NCWS should not only focus on whether gluten may be a potential trigger but also on managing patient expectations and perceptions related to intake. For those without CD or WA who choose to follow a gluten-free diet, ensure patients receive adequate support to avoid unbalanced dietary intake, nutritional deficiencies and excess psychological and financial burden.