Background/Aim: Despite strict adherence to a gluten-free diet (GFD), many patients with celiac disease (CeD) experience persistent symptoms and impaired quality of life (QoL), termed nonresponsive celiac disease (NRCeD). The aryl hydrocarbon receptor (AhR) pathway is a ligand-activated transcriptional system involved in maintaining gastrointestinal homeostasis. Our previous work demonstrated that this pathway is impaired in CeD and is not completely normalized on a GFD. We, therefore, tested the hypothesis that oral L-tryptophan, an AhR ligand precursor, restores AhR signaling, improving clinical outcomes in adults with NRCeD.
Methods: Fifty participants were randomised in a double-blind, placebo-controlled trial to receive small intestinal release L-tryptophan (3 g/day; n=24) or placebo (n=26) for three weeks while following a tryptophan-controlled GFD. The primary outcome was clinically meaningful improvement (≥7 points) in the Celiac Symptom Index (CSI). Secondary outcomes included Hospital Anxiety and Depression Scale (HADS), Depression Anxiety Stress Scales-21 (DASS-21), and Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life (PAGI-QoL) scores, AhR activity in duodenal aspirates and stool, targeted tryptophan metabolites, and microbiota analysis.
Results: The primary outcome was not met as CSI improved in 50% of the L-tryptophan group versus 53% of placebo. However, L-tryptophan improved QoL (58% vs 15%; ANCOVA p=0.01), HADS-anxiety (46% vs 26%; ANCOVA p=0.04), and DASS-21 stress (42% vs 8%; ANCOVA p=0.03). L-tryptophan increased serum indole (p=0.01), indole-3-lactic acid (p=0.007), total indoles (p=0.003), and duodenal AhR activity (p=0.04). Exploratory microbiome analyses showed higher Agathobacter in aspirates and Lachnoclostridium in biopsies, with predicted functions consistent with enhanced microbial tryptophan metabolism and indole production.
Conclusion: These findings provide clinical evidence that oral L-tryptophan supplementation modulates the tryptophan-AhR pathway in NRCeD, with improvements in psychological symptoms and QoL, supporting larger, adequately powered trials with longer intervention periods and more sensitive symptom assessment tools.