Esophageal epithelial cell-derived kynurenine drives Th17 inflammation in reflux esophagitis and is targeted by Xuanfu Daizhe decoction.

Abstract

Background: The role of immunometabolic dysregulation in reflux esophagitis (RE), particularly the metabolic drivers of pathogenic T helper 17 (Th17) cell differentiation, is not fully understood. Although Xuanfu Daizhe Decoction (XDD) is a clinically effective Traditional Chinese Medicine (TCM) formula for RE, its potential to modulate these immunometabolic pathways remains unelucidated.

Objective: This study aimed to investigate the mechanism by which tryptophan metabolic dysregulation in RE influences Th17 cell differentiation and to evaluate whether XDD exerts therapeutic effects by targeting this pathway.

Methods: Metabolomic analysis was performed to assess alterations in the tryptophan metabolic pathway in serum from RE patients and RE rat models. Inflamed human esophageal epithelial cells (HEECs) model was established using acidified bile salts to observe kynurenine (KYN) secretion and its effect on Th17 differentiation. siRNA-mediated silencing of the aryl hydrocarbon receptor repressor (AHRR) was employed to clarify the role of AHRR in KYN-AhR-mediated Th17 differentiation. The interventional effects of XDD and its impact on the KYN-AHRR-AhR-Th17 axis were further examined in both cellular and rat models.

Results: Metabolomic profiling of clinical samples and RE rat models demonstrated significant dysregulation in the KYN pathway. Furthermore, we identified that inflamed HEECs induced high expression of IDO/TDO to elevate KYN secretion, which promoted Th17 cell differentiation. Mechanistically, KYN disrupted aryl hydrocarbon receptor (AhR) signaling via upregulation of its repressor, AHRR, thereby driving Th17 differentiation. Finally, we demonstrated that XDD treatment alleviated inflammation and tissue injury of RE by modulating the KYN-AHRR-AhR-Th17 axis.

Conclusion: This study reveals a novel mechanism in RE whereby esophageal epithelial-derived KYN promotes Th17 differentiation via the AHRR-AhR signaling axis. Furthermore, XDD exerts therapeutic effects by modulating this immunometabolic pathway. These findings provide new insights into RE pathogenesis and experimental evidence supporting the application of XDD in immunometabolic disorders.