肠道微生物群衍生的吲哚-3-乙酰胺介导巴氏杀菌嗜粘蛋白阿克曼菌对 5-氟尿嘧啶诱导的小鼠粘膜炎的保护作用

化疗诱导的肠粘膜炎 （CIM） 是癌症治疗中的主要剂量限制性毒性。肠道微生物群调节提供了一种有前途的缓解 CIM 的策略，但嗜粘蛋白阿克曼菌的作用仍不清楚。在这里，我们评估了活 （Akk） 和巴氏杀菌嗜粘蛋白不动杆菌 （pAkk） 在 5-氟尿嘧啶 （5-FU） 诱导的 CIM 小鼠模型中的保护作用。两种治疗都显着减少了肠道损伤、炎症和氧化应激，其中 pAkk 在增强肠道屏障功能方面显示出卓越的功效。来自 pAkk 处理的小鼠的粪便微生物群或不育粪便滤液 （SFF） 在抗生素处理的受体中复制了保护作用，表明微生物群衍生因子的贡献。16S rRNA 测序和非靶向代谢组学确定吲哚-3-乙酰胺 （IAM） 是 pAkk 升高的关键代谢物。体外发酵和细胞实验证实，IAM 激活芳烃受体 （AHR），抑制 MLCK 信号传导，并上调紧密连接蛋白，从而增强屏障完整性。这些发现表明，pAkk 通过微生物群衍生的 IAM 缓解 CIM，为化疗引起的并发症的后生元干预提供了新的见解。

Chemotherapy-induced intestinal mucositis (CIM) is a major dose-limiting toxicity in cancer therapy. Gut microbiota modulation provides a promising strategy for alleviating CIM, but the role of Akkermansia muciniphila remains unclear. Here, we evaluated the protective effects of live (Akk) and pasteurized A. muciniphila (pAkk) in a 5-fluorouracil (5-FU)-induced CIM mouse model. Both treatments significantly reduced intestinal injury, inflammation and oxidative stress, with pAkk demonstrating superior efficacy in enhancing intestinal barrier function. Fecal microbiota or sterile fecal filtrate (SFF) from pAkk-treated mice replicated the protective effects in antibiotic-treated recipients, indicating the contribution of microbiota-derived factors. 16S rRNA sequencing and untargeted metabolomics identified indole-3-acetamide (IAM) as a key metabolite elevated by pAkk. In vitro fermentation and cellular experiments confirmed that IAM activates the aryl hydrocarbon receptor (AHR), inhibits MLCK signaling, and upregulates tight junction proteins, thereby enhancing barrier integrity. These findings demonstrate that pAkk alleviates CIM via microbiota-derived IAM, providing novel insights into postbiotic interventions for chemotherapy-induced complications.