Mitochondrial perturbation in the intestine causes microbiota-dependent injury and gene signatures discriminative of inflammatory disease

IF 20.6 1区 医学 Q1 MICROBIOLOGY Cell host & microbe Pub Date : 2024-07-15 DOI:10.1016/j.chom.2024.06.013
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Abstract

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 (Hsp60Δ/ΔIEC). This metabolic perturbation causes self-resolving tissue injury. Regeneration is disrupted in the absence of the aryl hydrocarbon receptor (Hsp60Δ/ΔIEC;AhR−/−) involved in intestinal homeostasis or inflammatory regulator interleukin (IL)-10 (Hsp60Δ/ΔIEC;Il10−/−), causing IBD-like pathology. Injury is absent in the distal colon of germ-free (GF) Hsp60Δ/ΔIEC mice, highlighting bacterial control of metabolic injury. Colonizing GF Hsp60Δ/ΔIEC mice with the synthetic community OMM12 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.

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肠道线粒体扰动导致微生物群依赖性损伤和炎症性疾病鉴别基因特征
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(Hsp60Δ/ΔIEC)来破坏上皮细胞的线粒体功能。这种新陈代谢扰动会导致组织损伤的自我修复。在缺乏参与肠道稳态的芳基烃受体(Hsp60Δ/ΔIEC;AhR-/-)或炎症调节因子白细胞介素(IL)-10(Hsp60Δ/ΔIEC;Il10-/-)的情况下,组织再生会受到破坏,从而导致类似 IBD 的病理变化。无菌(GF)Hsp60Δ/ΔIEC 小鼠的远端结肠不存在损伤,这突显了细菌对代谢损伤的控制。用合成群落 OMM12 对 GF Hsp60Δ/ΔIEC 小鼠进行定殖,发现代谢灵活的乳酸杆菌扩增,而粪肠球菌的单一定殖再现了损伤。代谢受损上皮细胞的转录谱分析揭示了涉及氧化应激的基因特征(Ido1、Nos2、Duox2)。在克罗恩病患者的样本中也能观察到这些特征,从而区分活动性和非活动性炎症。因此,上皮细胞的线粒体扰乱会导致微生物群依赖性损伤,并产生与 IBD 相关的可区分的炎症基因特征。
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来源期刊
Cell host & microbe
Cell host & microbe 生物-微生物学
CiteScore
45.10
自引率
1.70%
发文量
201
审稿时长
4-8 weeks
期刊介绍: Cell Host & Microbe is a scientific journal that was launched in March 2007. The journal aims to provide a platform for scientists to exchange ideas and concepts related to the study of microbes and their interaction with host organisms at a molecular, cellular, and immune level. It publishes novel findings on a wide range of microorganisms including bacteria, fungi, parasites, and viruses. The journal focuses on the interface between the microbe and its host, whether the host is a vertebrate, invertebrate, or plant, and whether the microbe is pathogenic, non-pathogenic, or commensal. The integrated study of microbes and their interactions with each other, their host, and the cellular environment they inhabit is a unifying theme of the journal. The published work in Cell Host & Microbe is expected to be of exceptional significance within its field and also of interest to researchers in other areas. In addition to primary research articles, the journal features expert analysis, commentary, and reviews on current topics of interest in the field.
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