Targeted Dietary Exclusion Using Confocal Laser Endomicroscopy Does Not Improve Symptom Burden in Functional Dyspepsia: Results From a Randomized, Double‐Blind, Sham‐Controlled, Cross‐Over Study

ABSTRACT Background and Aims In functional dyspepsia (FD), symptoms may arise from impaired duodenal barrier function and mucosal immune activation. Confocal laser endomicroscopy (CLE) visualizes acute food‐induced mucosal alterations of the duodenal epithelium in response to locally‐applied food solutions in vivo, but their link with permeability, immune activation, and response to diet is unclear. Methods In a randomized, double‐blind, crossover, sham‐controlled trial, 17 Rome IV FD patients without food‐specific IgE underwent baseline endoscopy and 29 CLE procedures with local nutrient exposure. Transepithelial electrical resistance, serum tryptase, and tryptase/eosinophil‐derived neurotoxin release from biopsies were assessed. Patients completed CLE‐guided (real) and sham exclusion diets in a randomized blinded order. Clinical response was defined as ≥ 0.7 decrease in Leuven Postprandial Distress Scale (LPDS). Results CLE showed acute mucosal alterations in 16/17 patients. These were not associated with changes in permeability, systemic tryptase, or tryptase/EDN release from biopsies (all p > 0.05). In 14 evaluable patients, clinical response rates did not differ between real and sham diets (4/14 vs. 2/14, p = 0.41). As a secondary analysis, no differences were found across LPDS subdomains or PAGI‐SYM scores. Conclusion CLE detects a high frequency of food‐induced duodenal changes in FD, but these do not correlate with barrier or immune markers and do not predict dietary benefit. CLE‐based elimination diets cannot be recommended for FD.