Non-celiac gluten/wheat sensitivity (NCGS)

Pathogenesis of gluten/wheat sensitivity

The precise pathogenic mechanisms underlying gluten/wheat sensitivity—also known as non-celiac wheat sensitivity (NCWS) or non-celiac gluten sensitivity (NCGS)—remain incompletely understood. However, it is well established that the condition does not involve autoimmune responses like celiac disease or classical allergic reactions.

Immunological mechanisms in gluten/wheat sensitivity

While the pathogenesis of gluten/wheat sensitivity is not fully elucidated, current evidence highlights a pivotal role for the innate immune system. Intestinal biopsies from affected individuals have demonstrated elevated expression of Toll-like receptor 2 (TLR2), which is involved in recognizing gluten components and initiating inflammatory responses, alongside reduced expression of FOXP3, a transcription factor essential for regulatory T cell development and immune tolerance.

Gluten sensitivity: evidence of intestinal inflammation

Inflammatory alterations have been identified in both the small and large intestines of affected individuals. Although villous atrophy typical of celiac disease is absent, many patients exhibit a modest increase in intraepithelial lymphocytes (IELs). Additionally, elevated mast cell counts in the duodenum have been correlated with more pronounced symptoms such as abdominal discomfort and bloating.

Gluten sensitivity: disruption of the intestinal barrier and microbiota

Research has revealed increased serum concentrations of soluble CD14, LPS-binding protein, and antibodies targeting microbial components such as lipopolysaccharide (LPS) and flagellin. These biomarkers are associated with elevated levels of intestinal fatty acid-binding protein (FABP2), indicating mucosal damage. Furthermore, evidence of intestinal dysbiosis has been documented in individuals with gluten/wheat sensitivity.

Gluten sensitivity: causes between gluten, ATIs, and FODMAPs

The role of gluten as the exclusive trigger for symptoms remains contentious. A recent systematic review found that only 8 out of 16 double-blind, placebo-controlled trials demonstrated a significantly greater symptom response to gluten compared to placebo.

Consequently, attention has shifted toward other wheat constituents. Wheat is rich in fructans, a type of fermentable oligosaccharide (FODMAP), which may contribute to symptoms. Low-FODMAP diets have shown efficacy, particularly in patients with irritable bowel syndrome whose symptoms overlap with NCWS. Studies suggest that combining a gluten-free and low-FODMAP diet may offer enhanced symptom relief.

Amylase-trypsin inhibitors (ATIs), which constitute approximately 2–4% of wheat proteins, are natural defense molecules found in cereal grains. These proteins resist enzymatic digestion, traverse the intestinal epithelium, and activate the innate immune system, prompting the release of proinflammatory cytokines such as IL-8, IL-15, and TNF-α. Although preclinical studies support their proinflammatory potential, controlled human trials directly linking ATIs to gluten/wheat sensitivity are currently lacking.

The role of the nocebo effect and expectations

Emerging research underscores the significant influence of patient expectations on symptom perception in gluten/wheat sensitivity. Participants who believed they were ingesting gluten reported more severe symptoms, regardless of actual gluten exposure. Conversely, individuals who unknowingly consumed gluten experienced milder symptoms, suggesting a substantial nocebo effect.

Current state of research

Current research does not conclusively identify specific wheat components—such as gluten, FODMAPs, or ATIs—as sole etiological agents of gluten/wheat sensitivity. Findings remain inconsistent and are often limited by methodological shortcomings. Moreover, the nocebo effect appears to play a critical role in symptom manifestation. Future investigations should employ standardized protocols, rigorously defined patient cohorts, and appropriate control groups to clarify pathogenesis. The identification of reliable biomarkers is essential to reduce diagnostic ambiguity and guide targeted therapeutic strategies.

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