Chair of Nutrition and Immunology, Technical University of Munich, Gregor-Mendel-Strasse 2, 85354 Freising, Germany.
Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, 80337 Munich, Germany.
Cell Host Microbe. 2024 Aug 14;32(8):1347-1364.e10. doi: 10.1016/j.chom.2024.06.013. Epub 2024 Jul 15.
Mitochondrial dysfunction is associated with inflammatory bowel diseases (IBDs). To understand how microbial-metabolic circuits contribute to intestinal injury, we disrupt mitochondrial function in the epithelium by deleting the mitochondrial chaperone, heat shock protein 60 (Hsp60). This metabolic perturbation causes self-resolving tissue injury. Regeneration is disrupted in the absence of the aryl hydrocarbon receptor (Hsp60;AhR) involved in intestinal homeostasis or inflammatory regulator interleukin (IL)-10 (Hsp60;Il10), causing IBD-like pathology. Injury is absent in the distal colon of germ-free (GF) Hsp60 mice, highlighting bacterial control of metabolic injury. Colonizing GF Hsp60 mice with the synthetic community OMM reveals expansion of metabolically flexible Bacteroides, and B. caecimuris mono-colonization recapitulates the injury. Transcriptional profiling of the metabolically impaired epithelium reveals gene signatures involved in oxidative stress (Ido1, Nos2, Duox2). These signatures are observed in samples from Crohn's disease patients, distinguishing active from inactive inflammation. Thus, mitochondrial perturbation of the epithelium causes microbiota-dependent injury with discriminative inflammatory gene profiles relevant for IBD.
线粒体功能障碍与炎症性肠病（IBD）有关。为了了解微生物代谢回路如何导致肠道损伤，我们通过敲除线粒体伴侣热休克蛋白 60（Hsp60）来破坏上皮细胞中的线粒体功能。这种代谢干扰会导致自限性组织损伤。在涉及肠道稳态的芳香烃受体（Hsp60；AhR）或炎症调节因子白细胞介素（IL）-10（Hsp60；Il10）缺失的情况下，再生会受到干扰，导致类似 IBD 的病理学。在无菌（GF）Hsp60 小鼠的远端结肠中，不存在损伤，这突出了细菌对代谢损伤的控制作用。用合成群落 OMM 定植 GF Hsp60 小鼠会导致代谢灵活的拟杆菌扩张，而 B. caecimuris 的单定植会重现损伤。对代谢受损的上皮细胞进行转录谱分析显示，与氧化应激相关的基因特征（Ido1、Nos2、Duox2）。在克罗恩病患者的样本中观察到这些特征，可将活跃炎症与非活跃炎症区分开来。因此，上皮细胞中线粒体的扰动会导致依赖微生物群的损伤，并伴有与 IBD 相关的具有鉴别性的炎症基因特征。
