The bitter flavor of Banxia Xiexin Decoction activates TAS2R38 to ameliorate low-grade inflammation in the duodenum of mice with functional dyspepsia

Ethnopharmacological relevance: Banxia Xiexin Decoction (BXD) is a traditional herbal formulation with a bitter flavor that has a long-standing history of use in Asia for treating functional dyspepsia (FD). In traditional Chinese medicine, the bitter flavor is believed to play a critical role in the therapeutic activity of BXD. The ethnopharmacological properties of bitter plant extracts are closely associated with their anti-inflammatory effects, which may contribute to their efficacy in FD. However, the specific mechanisms remain unknown.

Aim of the study: The objective of this study is to uncover the bitter active compounds of BXD and their effects in the treatment of FD.

Materials and methods: The chemical compounds of BXD were identified using HPLC-Q-Exactive-MS. Active compounds in BXD were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, and bitter active compounds were further identified using BitterDB and PlantMolecularTasteDB. Molecular docking was employed to identify potential targets of these bitter active compounds, and their activation was validated through flow cytometry analysis of Ca²⁺. Subsequently, a mouse model of FD was established, and our hypothesis was further validated using enzyme linked immunosorbent assay, immunohistochemistry, immunofluorescence, and western blotting.

Results: Through HPLC-Q-Exactive-MS analysis, TCMSP, BitterDB, and PlantMolecularTasteDB database, a total of 11 bitter active compounds in BXD were identified: Baicalein, Baicalin, Berberine, Coptisine, Formononetin, Isorhamnetin, Kaempferol, Naringenin, Palmatine, Quercetin, and Wogonin. Molecular docking results indicated that these active compounds exhibited strong affinity for TAS2R38, with Berberine showing the highest scoring. Flow cytometry analysis of Ca²⁺ revealed that both Berberine and BXD elevated intracellular calcium concentrations, although this effect was partially antagonized by the TAS2R38 inhibitor probenecid. In vivo experiments demonstrated that BXD effectively improved eosinophil infiltration in the duodenum of FD mice, downregulated the expression of inflammatory factors IL-1β, IL-5, and TNF-α, inhibition of NF-κB signaling pathway activation, alleviated damage to the duodenal mucosal barrier, and reversed gastrointestinal motility disorders, with the therapeutic effect enhancing with increasing doses of BXD. However, this therapeutic effect was partially inhibited following probenecid intervention.

Conclusion: BXD contains numerous bitter active compounds that play a significant role in regulating inflammatory activity in the duodenum of FD through the activation of TAS2R38. This finding unveils, for the first time, the ethnopharmacological activity of bitter plant taste agents in anti-inflammatory effects, providing new insights for the treatment and drug development of FD.