Salicylic Acid as a Food‐Derived Bioactive Constituent of Tiaoqi Daozhi Decoction: A Potential Functional Food Ingredient to Restoring Gut Barrier Function in Constipation‐Predominant IBS

ABSTRACT Constipation‐predominant irritable bowel syndrome (IBS‐C) is a chronic gut disorder with limited dietary management options. Tiaoqi Daozhi Decoction (TQDZD), composed of medicine‐food homologous plant materials traditionally consumed for digestive comfort, represents a dietary strategy with functional food potential, yet its systemically bioavailable constituents and nutritional mechanisms remain unclear. This study aimed to characterize the orally bioavailable polyphenol profile of TQDZD and elucidate its barrier‐protective mechanisms within a functional food framework. Using ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) serum metabolite profiling, we characterized TQDZD's polyphenol composition and identified orally bioavailable constituents in rat circulation after dietary administration. Untargeted serum metabolomics coupled with orthogonal partial least‐squares discriminant analysis (OPLS‐DA) was performed to map metabolic network perturbations in an IBS‐C rat model, and dietary bioactive pathways were predicted by comparing intervention‐induced metabolic trajectories. IBS‐C was induced in rats by ice‐water enema, and an in vitro inflammatory model was established using lipopolysaccharide (LPS)‐stimulated Caco‐2 monolayers. Barrier function was assessed by fluorescein isothiocyanate (FITC)‐dextran flux; tight junction proteins, cytokines, and signaling pathways were evaluated by Western blot, immunofluorescence, ELISA, and qPCR. To explore the mechanistic basis of the observed barrier‐protective effects, Bruton's tyrosine kinase (BTK) signaling involvement was assessed using siRNA‐mediated knockdown and plasmid‐mediated overexpression as complementary pharmacological tools. A total of 1962 non‐redundant compounds were identified in TQDZD aqueous extract, with phenolic acids and flavonoids as the predominant chemical classes. These polyphenol‐rich profiles are characteristic of functional foods with gut‐protective potential. In dosed rat serum, 257 systemically bioavailable components were detected, of which 150 (58.4%) were prototype constituents. Multi‐criteria screening (treatment/control peak area ratio ≥ 2, top‐20 abundance rank in the formula, coefficient of variation < 30%, and Level 1 identification confidence) yielded four core prototypes: salicylic acid, N‐acetyl‐L‐phenylalanine, L‐valyl‐L‐phenylalanine, and L‐phenylalanyl‐L‐hydroxyproline. Among these, salicylic acid—a naturally occurring phenolic acid widely distributed in plant‐based foods—was prioritized for functional validation. Untargeted metabolomics revealed that IBS‐C rats exhibited profound dysregulation of a lipid‐inflammatory network, characterized by disturbances in glycerophospholipid metabolism, linoleic acid metabolism, and sphingolipid signaling. TQDZD intervention remodeled this network in a dose‐dependent manner; notably, the metabolic trajectory of the high‐dose TQDZD group converged strikingly with that of the BTK modulator orelabrutinib. In vivo, TQDZD significantly reduced intestinal permeability ( p < 0.001), restored colonic expression of tight junction proteins zonula occludens‐1 (ZO‐1), Occludin, and Claudin‐1 ( p < 0.001), and suppressed mucosal and serum levels of tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), IL‐1β, and monocyte chemoattractant protein‐1 (MCP‐1) ( p < 0.001). Mechanistic studies demonstrated that Tiaoqi Daozhi Decoction (TQDZD) inhibited the BTK‐spleen tyrosine kinase (SYK)‐ phospholipase C gamma 2 (PLCγ2)‐protein kinase B (AKT) axis, thereby blocking IκBα phosphorylation and p65 nuclear translocation. BTK knockdown potentiated, whereas BTK overexpression abrogated, the barrier‐protective and anti‐inflammatory effects of TQDZD. Salicylic acid alone fully reproduced TQDZD's phenotype in vitro and in vivo, and its effects were strictly BTK‐dependent. TQDZD exerts its therapeutic effect on constipation‐predominant irritable bowel syndrome (IBS‐C) via its core systemically bioavailable constituent salicylic acid. The biological activity of salicylic acid relies on the BTK signaling pathway, which blocks the non‐canonical nuclear factor‐κB (NF‐κB) pathway, thereby restoring the intestinal epithelial barrier and suppressing low‐grade inflammation. Given salicylic acid's abundance in edible plants and its long history of safe dietary exposure, these findings provide a mechanistic rationale for developing phenolic‐acid‐rich botanical blends as supportive dietary strategies for IBS‐C and related barrier‐centric gastrointestinal disorders.