期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 17, 页码 9401-9412出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1913976117
关键词
stem cells; epithelial barrier defects; host-microbe homeostasis; JNK; Drosophila
资金
- Genomics and Proteomics Core Facility at the German Cancer Research Center
- Deutsche Forschungsgemeinschaft Collaborative Research Center [SFB873]
- Deutsche Forschungsgemeinschaft Excellence Cluster CellNetworks
- Imaging Core Facility at the German Cancer Research Center
In all animals, the intestinal epithelium forms a tight barrier to the environment. The epithelium regulates the absorption of nutrients, mounts immune responses, and prevents systemic infections. Here, we investigate the consequences of tumorigenesis on the microbiome using a Drosophila intestinal tumor model. We show that upon loss of BMP signaling, tumors lead to aberrant activation of JNK/Mmp2 signaling, followed by intestinal barrier dysfunction and commensal imbalance. In turn, the dysbiotic microbiome triggers a regenerative response and stimulates tumor growth. We find that inhibiting JNK signaling or depletion of the microbiome restores barrier function of the intestinal epithelium, leading to a reestablishment of host-microbe homeostasis, and organismic lifespan extension. Our experiments identify a JNK-dependent feedback amplification loop between intestinal tumors and the microbiome. They also highlight the importance of controlling the activity level of JNK signaling to maintain epithelial barrier function and host-microbe homeostasis.
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