IDO1 integrates gut microbiota-derived SCFAs signals and host WNT/TGF-β pathways to mediate the anti-colorectal cancer effects of licorice flavonoids.

Licorice flavonoids (LF), bioactive components of Glycyrrhiza uralensis Fisch, exhibit promising anti-colorectal cancer (CRC) potential. However, the mechanism by which LF inhibits CRC remains unclear. In this study, we attempt to elucidate how indoleamine 2,3-dioxygenase 1 (IDO1) functions as a convergent downstream effector of both microbiota-derived signals and host oncogenic pathways in order to mediate the chemopreventive effects of LF on CRC. Using AOM/DSS and Apcmin/+ CRC mice models and colonic epithelial cells, we combined 16S rRNA sequencing, metabolomics, transcriptomics, and functional assays including IDO1 knockout, fecal microbiota transplantation, and antibiotic treatment. LF markedly inhibited colorectal tumorigenesis and restored intestinal barrier integrity. Mechanistically, LF remodeled the gut microbiota to enrich SCFAs‑producing genera, including Parabacteroides, Paramuribaculum, and Parasutterella, thereby increasing the levels of SCFAs such as butyric acid, isobutyric acid, valeric acid, and isovaleric acid in feces. These SCFAs downregulated IDO1 in CRC cells, and genetic ablation of IDO1 largely abolished SCFAs‑induced anti‑proliferative effects, establishing IDO1 as a critical downstream mediator. This regulation rewired tryptophan metabolism, reducing kynurenine metabolites and elevating microbiota-related indoles. Notably, the protective effect of LF against CRC was substantially diminished in IDO1‑knockout mice, underscoring IDO1 as a critical mediator. Additionally, LF treatment was associated with suppression of WNT/TGF‑β signaling. Collectively, these results identify IDO1 as a critical downstream effector that responds to the regulation of gut microbiota-SCFAs signaling and host WNT/TGF‑β pathways by LF, suggesting that LF‑induced IDO1 inhibition may represent a promising translational strategy for CRC prevention through concurrent modulation of microbial and host pathways.