Molecular Triggers of Non-celiac Wheat Sensitivity: A Scoping Review and Analysis.

INTRODUCTION

Nonceliac wheat sensitivity (NCWS) is characterized by a symptomatic response to the ingestion of foods containing wheat and related cereal grains in the absence of celiac disease or wheat allergy. Despite efforts to identify the constituent component(s) of wheat responsible for triggering NCWS, no consensus has emerged, leading to competing claims. We aimed to systematically evaluate the literature and provide an evidence-based conclusion on the contribution of specific wheat components to NCWS.

METHODS

A comprehensive search of multiple bibliographic databases was conducted, focusing on primary research. Data were systematically analyzed, and methodological gaps were identified.

RESULTS

The search identified 175 unique citations, revealing 3 categories of compounds frequently considered as potential triggers of NCWS: gluten, fermentable carbohydrates, and amylase/trypsin inhibitors (ATIs). Among 16 double-blind placebo-controlled studies, 8 reported a greater symptomatic response to gluten than the control. Only 1 controlled study examined fermentable carbohydrates, finding a modest effect, but the tested carbohydrates were not derived from wheat. No eligible studies assessed ATIs or other wheat-related compounds as potential NCWS triggers. Across studies, significant limitations and methodological inconsistencies were noted, particularly in participant selection, challenge protocols, and data reporting.

DISCUSSION

Gluten is the most extensively investigated wheat component linked to NCWS, but evidence for its role is inconsistent and undermined by methodological limitations. No direct evidence currently links wheat fermentable carbohydrates, ATIs, or other components to NCWS symptoms. The existing evidence is insufficient to justify restricting specific components of wheat in the management of NCWS. Future studies must overcome the identified gaps to rigorously investigate the role of wheat and related cereals in NCWS, with the potential to advance diagnosis and treatment.

Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.