Taxifolin ameliorates radiation-induced colitis via the gut microbiota-BAs-FXR/NLRP3 axis

Radiation-induced colitis (RC) poses a substantial clinical challenge with limited therapeutic options. Taxifolin (TAX), a natural flavonoid, exhibits potential anti-inflammatory properties; however, its clinical application is hindered by poor oral bioavailability and an unclear mechanism of action in the context of radiation injury.

This study aims to investigate the therapeutic potential and underlying mechanisms of the flavonoid monomer TAX in the context of RC, with a particular focus on the gut microbiota-BAs-FXR/NLRP3 axis.

We employed a 13 Gy total abdominal irradiation (TAI) mouse model and HIEC-6 cells. Multi-omics approaches, including 16S rRNA sequencing and untargeted metabolomics, were used to map microbiota and metabolic profiles. Crucially, to establish causality, fecal microbiota transplantation (FMT) was performed to assess the microbiota's mediating role, and the specific FXR antagonist DY268 was utilized to verify the dependency on FXR signaling. Molecular interactions were confirmed via molecular docking, drug affinity responsive target stability (DARTS), and co-immunoprecipitation (Co-IP) assays.

TAX significantly mitigated RC, characterized by preserved intestinal barrier integrity and reduced inflammatory cytokine production. It reshaped microbial homeostasis, specifically enriching bile acid (BA)-metabolizing genera (such as Lachnoclostridium) and promoting the accumulation of specific FXR-activating BAs, including glycocholic acid (GCA), taurochenodeoxycholic acid (TCDCA), and ursodeoxycholic acid (UDCA). FMT from TAX-treated donors successfully recapitulated the radioprotective phenotype in recipient mice, confirming the causal role of the gut microbiota. Mechanistically, both TAX and the enriched BAs directly bound to the farnesoid X receptor (FXR), inducing conformational changes that enhanced its physical interaction with NLRP3, thereby inhibiting inflammasome assembly and downstream signaling. Importantly, pharmacological blockade of FXR by DY268 abolished the protective effects of TAX, confirming that FXR activation is indispensable for its therapeutic action.

TAX mitigates RC not merely as an antioxidant, but as a microecological modulator. Importantly, TAX acts as a natural modulator of the "gut microbiota-BAs-FXR/NLRP3" signaling axis for RC therapy. TAX-induced microbiota changes promote the production of specific bile acids that amplify intestinal FXR signaling to suppress inflammation. This study provides a robust mechanistic basis for using TAX as an orally active radioprotectant targeting the gut-liver axis.