Psyllium Fiber Enhances Intestinal Antimicrobial Protein Expression via a Tuft Cell–ILC2 Axis in a Microbiota-Independent Manner

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 the tuft cell chemosensory channel TRPM5 suppressed psyllium-induced type 2 immune signaling and AMP expression, indicating that chemosensory transduction is required. Enzymatic degradation of psyllium markedly reduced tuft cell activation and downstream AMP induction, demonstrating dependence on fiber structural integrity. Notably, psyllium-induced SPRR2A and RELMβ expression and type 2 immune signaling persisted during broad-spectrum antibiotic treatment, supporting a microbiota-independent mechanism. In murine intestinal organoids, IL-13 directly induced SPRR2A and RELMβ via the JAK1/2–STAT6 pathway, and promoter analyses identified functional STAT6-binding sites that are essential for Sprr2a transcription. Together, these findings define a microbiota-independent pathway by which psyllium strengthens intestinal barrier defense via tuft cell–ILC2–IL-13 signaling.