Coix seed as a microbiota-targeted functional food: Postbiotic inosine mediates protection against chemotherapy-induced intestinal mucositis

5-Fluorouracil (5-FU)-induced intestinal mucositis (IM) is a dose-limiting complication of chemotherapy that severely compromises patient quality of life and treatment adherence. Coix seed (CS), a traditional cereal grain with established “medicine food homology” status in East Asia, has demonstrated potential benefits for intestinal health. However, the protective mechanisms of this functional food against chemotherapy-induced gastrointestinal toxicity remain unexplored. Here, we demonstrate for the first time that dietary CS supplementation effectively alleviates 5-FU-induced IM without compromising antitumor efficacy. Integrated 16S rDNA sequencing revealed that CS ameliorated 5-FU-induced gut microbiota dysbiosis by suppressing pathogenic bacteria while enriching beneficial commensals. Transcriptomic analysis identified the PI3K/Akt-NF-κB pathway as the key inflammatory cascade inhibited by CS. Notably, untargeted metabolomics demonstrated that CS promoted the accumulation of gut microbiota-derived inosine, a postbiotic purine metabolite. In vitro anaerobic fermentation confirmed that CS serves as a fermentable substrate for beneficial bacteria to produce inosine. Importantly, exogenous inosine administration recapitulated the gastroprotective effects of CS by suppressing PI3K/Akt-NF-κB-mediated inflammation through adenosine A₁ receptor activation. These findings establish a novel “diet-microbiota-metabolite-health” axis linking dietary CS intake to intestinal protection, providing scientific evidence for developing microbiota-targeted functional foods for the nutritional management of chemotherapy-induced IM.