Zhang Shuning, Peng Lihua, Goswami Shyamal, Li Yuchen, Dang Haiyue, Xing Shuli, Feng Panpan, Nigro Giulia, Liu Yingying, Ma Yingfei, Liu Tianhao, Yang Jiahua, Jiang Tinglei, Yang Yingnan, Barker Nick, Sansonetti Philippe, Kundu Parag
Laboratory for Microbiota-Host Interactions, The Center for Microbes, Development and Health, Shanghai Institute of Immunity and Infection-Chinese Academy of Sciences, Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China.
Nat Microbiol. 2025 Mar;10(3):765-783. doi: 10.1038/s41564-025-01937-5. Epub 2025 Feb 19.
Intestinal crypts harbour a specific microbiota but whether and how these bacteria regulate intestinal stem cells (ISCs) or influence colorectal cancer (CRC) development is unclear. Here we screened crypt-resident bacteria in organoids and found that indole acetic acid (IAA) secreted by Acinetobacter radioresistens inhibits ISC turnover. A. radioresistens inhibited cellular proliferation in tumour slices from CRC patients and inhibited intestinal tumorigenesis and spheroid initiation in APC mice. Targeted clearance of A. radioresistens from colonic crypts using bacteriophage increased EphB2 expression and consequently promoted cellular proliferation, ISC turnover and tumorigenesis in mouse models of CRC. The protective effects of A. radioresistens were abrogated upon deletion of trpC to prevent IAA production, or upon intestine-specific aryl hydrocarbon receptor (AhR) knockout, identifying an IAA-AhR-Wnt-β-catenin signalling axis that promotes ISC homeostasis. Our findings reveal a protective role for an intestinal crypt-resident microbiota member in tumorigenesis.
肠道隐窝中存在特定的微生物群，但这些细菌是否以及如何调节肠道干细胞（ISC）或影响结直肠癌（CRC）的发展尚不清楚。在这里，我们在类器官中筛选了隐窝驻留细菌，发现抗辐射不动杆菌分泌的吲哚乙酸（IAA）抑制ISC更新。抗辐射不动杆菌抑制CRC患者肿瘤切片中的细胞增殖，并抑制APC小鼠的肠道肿瘤发生和球体形成。使用噬菌体从结肠隐窝中靶向清除抗辐射不动杆菌可增加EphB2表达，从而促进CRC小鼠模型中的细胞增殖、ISC更新和肿瘤发生。删除trpC以阻止IAA产生，或在肠道特异性芳烃受体（AhR）敲除后，抗辐射不动杆菌的保护作用被消除，从而确定了促进ISC稳态的IAA-AhR-Wnt-β-连环蛋白信号轴。我们的研究结果揭示了肠道隐窝驻留微生物群成员在肿瘤发生中的保护作用。
