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Mitochondrial perturbation in the intestine causes microbiota-dependent injury and gene signatures discriminative of inflammatory disease
Cell Host & Microbe ( IF 20.6 ) Pub Date : 2024-07-15 , DOI: 10.1016/j.chom.2024.06.013 Elisabeth Urbauer 1 , Doriane Aguanno 1 , Nora Mindermann 1 , Hélène Omer 1 , Amira Metwaly 1 , Tina Krammel 1 , Tim Faro 2 , Marianne Remke 3 , Sandra Reitmeier 1 , Stefanie Bärthel 4 , Johannes Kersting 5 , Zihua Huang 5 , Feng Xian 6 , Manuela Schmidt 6 , Dieter Saur 4 , Samuel Huber 7 , Bärbel Stecher 8 , Markus List 9 , David Gómez-Varela 6 , Katja Steiger 3 , Matthieu Allez 10 , Eva Rath 1 , Dirk Haller 11
Cell Host & Microbe ( IF 20.6 ) Pub Date : 2024-07-15 , DOI: 10.1016/j.chom.2024.06.013 Elisabeth Urbauer 1 , Doriane Aguanno 1 , Nora Mindermann 1 , Hélène Omer 1 , Amira Metwaly 1 , Tina Krammel 1 , Tim Faro 2 , Marianne Remke 3 , Sandra Reitmeier 1 , Stefanie Bärthel 4 , Johannes Kersting 5 , Zihua Huang 5 , Feng Xian 6 , Manuela Schmidt 6 , Dieter Saur 4 , Samuel Huber 7 , Bärbel Stecher 8 , Markus List 9 , David Gómez-Varela 6 , Katja Steiger 3 , Matthieu Allez 10 , Eva Rath 1 , Dirk Haller 11
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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 , and mono-colonization recapitulates the injury. Transcriptional profiling of the metabolically impaired epithelium reveals gene signatures involved in oxidative stress (, , ). 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.
中文翻译：
肠道线粒体扰动导致微生物群依赖性损伤和区分炎症性疾病的基因特征
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，我们通过删除线粒体伴侣热休克蛋白 60 (Hsp60) 来破坏上皮中的线粒体功能。这种代谢紊乱会导致自愈性组织损伤。如果缺乏参与肠道稳态的芳烃受体 (Hsp60;AhR) 或炎症调节剂白细胞介素 (IL)-10 (Hsp60;Il10)，则再生会受到破坏，从而导致 IBD 样病理。无菌 (GF) Hsp60 小鼠的远端结肠不存在损伤，凸显了细菌对代谢损伤的控制。用合成群落 OMM 定植 GF Hsp60 小鼠，揭示了代谢灵活性的扩展，并且单定植再现了损伤。代谢受损上皮的转录谱揭示了参与氧化应激的基因特征 (, , )。这些特征是在克罗恩病患者的样本中观察到的，可区分活动性炎症和非活动性炎症。因此，上皮细胞的线粒体扰动会导致微生物群依赖性损伤，并具有与 IBD 相关的辨别性炎症基因谱。
更新日期：2024-07-15
中文翻译：
肠道线粒体扰动导致微生物群依赖性损伤和区分炎症性疾病的基因特征
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，我们通过删除线粒体伴侣热休克蛋白 60 (Hsp60) 来破坏上皮中的线粒体功能。这种代谢紊乱会导致自愈性组织损伤。如果缺乏参与肠道稳态的芳烃受体 (Hsp60;AhR) 或炎症调节剂白细胞介素 (IL)-10 (Hsp60;Il10)，则再生会受到破坏，从而导致 IBD 样病理。无菌 (GF) Hsp60 小鼠的远端结肠不存在损伤，凸显了细菌对代谢损伤的控制。用合成群落 OMM 定植 GF Hsp60 小鼠，揭示了代谢灵活性的扩展，并且单定植再现了损伤。代谢受损上皮的转录谱揭示了参与氧化应激的基因特征 (, , )。这些特征是在克罗恩病患者的样本中观察到的，可区分活动性炎症和非活动性炎症。因此，上皮细胞的线粒体扰动会导致微生物群依赖性损伤，并具有与 IBD 相关的辨别性炎症基因谱。
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