Multi-criteria screening, requiring a treatment-to-control peak area ratio of at least 2, a top-20 abundance rank in the formula, a coefficient of variation below 30 percent, and Level 1 identification confidence, narrowed the field to four core prototypes: salicylic acid, N-acetyl-L-phenylalanine, L-valyl-L-phenylalanine, and L-phenylalanyl-L-hydroxyproline. Salicylic acid was prioritized for functional validation because of its natural abundance in plant-based foods and long history of safe dietary exposure.

The animal model of IBS-C was induced by ice-water enema, and a complementary in vitro model used lipopolysaccharide-stimulated Caco-2 monolayers to assess barrier function through FITC-dextran flux. Untargeted serum metabolomics coupled with orthogonal partial least-squares discriminant analysis revealed that IBS-C rats showed profound dysregulation of a lipid-inflammatory network, involving glycerophospholipid metabolism, linoleic acid metabolism, and sphingolipid signaling. TQDZD intervention remodeled this network in a dose-dependent manner, and notably, the metabolic trajectory of the high-dose group converged strikingly with that of the BTK modulator orelabrutinib, pointing to Bruton’s tyrosine kinase as a central mechanistic node.

In vivo, TQDZD significantly reduced intestinal permeability, restored colonic expression of the tight junction proteins ZO-1, Occludin, and Claudin-1, and suppressed mucosal and serum levels of the inflammatory mediators TNF-α, IL-6, IL-1β, and MCP-1, all with p values below 0.001. Mechanistic experiments showed that the decoction inhibited the BTK–SYK–PLCγ2–AKT axis, blocking IκBα phosphorylation and p65 nuclear translocation, the non-canonical NF-κB cascade that drives inflammatory cytokine release. BTK knockdown by siRNA potentiated these effects, whereas plasmid-mediated BTK overexpression abrogated them, confirming strict BTK dependence.

Salicylic acid alone fully reproduced the decoction’s phenotype both in vitro and in vivo, and its activity was likewise BTK-dependent. Beyond suppressing cytokine release, the compound attenuated mast cell degranulation and CD19+ B cell infiltration, while simultaneously upregulating tight junction proteins and reducing FITC-dextran permeability, thereby restoring intestinal epithelial barrier integrity. The authors conclude that 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, within a functional food framework rather than as a drug therapy.

Subject of Research: Identification of salicylic acid as the bioavailable constituent of Tiaoqi Daozhi Decoction that restores gut barrier function in constipation-predominant IBS via BTK signaling

Article Title: 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

Article References: Duan, M., Huang, L., Xu, Y., Huang, Y., & Yang, X. (2026). 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. Food Science & Nutrition, 14(11), Article e72483. https://doi.org/10.1002/fsn3.72483

Image Credits: AI Generated

DOI: 10.1002/fsn3.72483

Keywords: salicylic acid, Tiaoqi Daozhi Decoction, irritable bowel syndrome, IBS-C, gut barrier, BTK signaling, NF-kB, tight junctions, polyphenols, functional food, intestinal permeability, metabolomics