Microbial-induced Redox Imbalance in the Neonatal Lung Is Ameliorated by Live Biotherapeutics.
Microbial-induced Redox Imbalance in the Neonatal Lung Is Ameliorated by Live Biotherapeutics.
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DOI：
10.1165/rcmb.2021-0508oc
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发表时间：
2023-03
影响因子：
6.4
通讯作者：
中科院分区：
文献类型：
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作者：
支气管肺发育不良（BPD）是早产儿常见的肺部疾病。高氧暴露和微生物生态失调是BPD发展的贡献者。然而，将肺部微生物生态失调与肺损伤恶化联系起来的机制尚不清楚。核因子红细胞2相关因子2（nuclear factor erythroid 2-related factor 2，nrf 2）是一种调节氧化应激反应和高氧诱导肺损伤的转录因子。我们假设气道生态失调会减弱Nrf 2依赖的抗氧化功能，导致更严重的BPD表型。在这里，我们表明，早产儿与γ-变形杆菌为主的生态失调增加气管吸出物中的内毒素，和小鼠单菌落与代表性的γ-变形杆菌大肠杆菌显示增加的组织损伤相比，无菌（GF）对照小鼠。此外，我们发现，当呼吸道微生物组被大肠杆菌增强时，Nrf 2缺陷小鼠在暴露于高氧后具有更差的肺结构和功能。杆菌为了证实气道生态失调的疾病引发潜力，我们开发了一种新的人源化小鼠模型，通过用患有或不患有严重BPD的人类婴儿的气管吸出物定殖GF小鼠，产生具有BPD相关和非BPD相关肺微生物组的gnotobiotic小鼠。与GF和非BPD相关小鼠相比，高氧暴露后，BPD相关小鼠表现出更严重的BPD表型和Nrf 2调节基因的表达增加。此外，通过支持乳杆菌属物种的定植来增强Nrf 2介导的抗氧化活性，改善了生态失调增强的肺损伤。我们的研究结果表明，缺乏保护性肺部微生物组特征会减弱Nrf 2介导的抗氧化反应，而呼吸道益生菌混合物会增强这种反应。我们预计抗氧化途径将成为未来基于微生物组的呼吸系统疾病治疗的主要目标。
Bronchopulmonary dysplasia (BPD) is a common lung disease of premature infants. Hyperoxia exposure and microbial dysbiosis are contributors to BPD development. However, the mechanisms linking pulmonary microbial dysbiosis to worsening lung injury are unknown. Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that regulates oxidative stress responses and modulates hyperoxia-induced lung injury. We hypothesized that airway dysbiosis would attenuate Nrf2-dependent antioxidant function, resulting in a more severe phenotype of BPD. Here, we show that preterm infants with a Gammaproteobacteria-predominant dysbiosis have increased endotoxin in tracheal aspirates, and mice monocolonized with the representative Gammaproteobacteria Escherichia coli show increased tissue damage compared with germ-free (GF) control mice. Furthermore, we show Nrf2-deficient mice have worse lung structure and function after exposure to hyperoxia when the airway microbiome is augmented with E. coli. To confirm the disease-initiating potential of airway dysbiosis, we developed a novel humanized mouse model by colonizing GF mice with tracheal aspirates from human infants with or without severe BPD, producing gnotobiotic mice with BPD-associated and non–BPD-associated lung microbiomes. After hyperoxia exposure, BPD-associated mice demonstrated a more severe BPD phenotype and increased expression of Nrf2-regulated genes, compared with GF and non–BPD-associated mice. Furthermore, augmenting Nrf2-mediated antioxidant activity by supporting colonization with Lactobacillus species improved dysbiotic-augmented lung injury. Our results demonstrate that a lack of protective pulmonary microbiome signature attenuates an Nrf2-mediated antioxidant response, which is augmented by a respiratory probiotic blend. We anticipate antioxidant pathways will be major targets of future microbiome-based therapeutics for respiratory disease.
影响因子：
4.6
作者：
Cho HY;Wang X;Li J;Bell DA;Kleeberger SR
通讯作者：
Kleeberger SR