Psyllium fiber enhances intestinal antimicrobial protein expression through bitter taste receptor-associated tuft cell–ILC2 signaling

Dietary fibers are generally thought to benefit gut health primarily through microbial fermentation. Our previous work demonstrated that dietary supplementation with psyllium fiber increases the production of the antimicrobial proteins (AMPs) SPRR2A and RELMβ in the mouse small intestine; however, the underlying mechanism remained unclear. Here, we show that psyllium induces AMP production through a tuft cell–ILC2 axis. Psyllium increased Il25 and Il13 mRNA expression, STAT6 phosphorylation, and AMP expression in the mouse small intestine, whereas these responses were abrogated in tuft cell-deficient Pou2f3 -knockout mice. Pharmacological inhibition of TRPM5-associated chemosensory signaling and bitter taste receptors suppressed psyllium-induced type 2 immune activation and AMP expression. Moreover, intracellular calcium assays in HEK293T cells expressing mouse Tas2rs identified Tas2r107 and Tas2r129 as candidate receptors responsive to psyllium, suggesting that bitter taste receptor-mediated sensing contributes to psyllium recognition. Enzymatic degradation of psyllium reduced tuft cell activation and AMP induction, demonstrating dependence on fiber structural integrity. Psyllium-induced responses persisted during broad-spectrum antibiotic treatment, supporting a largely microbiota-independent mechanism. In intestinal organoids, IL-13 induced SPRR2A and RELMβ expression via JAK1/2–STAT6 signaling. Together, these findings define a pathway by which psyllium strengthens intestinal barrier defense through bitter taste receptor-associated tuft cell–ILC2–IL-13 signaling.