Gut-Resident Lactobacilli Activate Hepatic Nrf2 and Protect Against Oxidative Liver Injury

Saeedi Bejan J.; Liu Ken H.; Owens Joshua A.; Hunter-Chang Sarah; Camacho Mary C.; Eboka Richard U.; Chandrasekharan Bindu; Baker Nusaiba F.; Darby Trevor M.; Robinson Brian S.; Jones Rheinallt M.; Jones Dean P.; Neish Andrew S.

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Gut-Resident Lactobacilli Activate Hepatic Nrf2 and Protect Against Oxidative Liver Injury

机译：肠道植物乳酸杆菌激活肝脏NRF2并防止氧化肝损伤

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Many studies have suggested a role for gut-resident microbes (the "gut microbiome'') in modulating host health; however, the mechanisms by which they impact systemic physiology remain largely unknown. In this study, metabolomic and transcriptional profiling of germ-free and conventionalized mouse liver revealed an upregulation of the Nrf2 antioxidant and xenobiotic response in microbiome-replete animals. Using a Drosophila-based screening assay, we identified members of the genus Lactobacillus capable of stimulating Nrf2. Indeed, the human commensal Lactobacillus rhamnosus GG (LGG) potently activated Nrf2 in the Drosophila liver analog and the murine liver. This activation was sufficient to protect against two models of oxidative liver injury, acetaminophen overdose and acute ethanol toxicity. Characterization of the portal circulation of LGG-treated mice by tandemmass spectrometry identified a small molecule activator of Nrf2, 5-methoxyindoleacetic acid, produced by LGG. Taken together, these data demonstrate a mechanism by which intestinal microbes modulate hepatic susceptibility to oxidative injury.

机译：许多研究表明，肠道常驻微生物（“肠道微生物组”）发挥了作用调节宿主健康；然而，它们影响系统生理学的机制仍基本未知。在这项研究中，对无菌和常规小鼠肝脏的代谢组学和转录谱分析显示，在充满微生物的动物中，Nrf2抗氧化剂和外源性反应上调。利用基于果蝇的筛选试验，我们鉴定了能够刺激Nrf2的乳杆菌属成员。事实上，人类共生鼠李糖乳杆菌GG（LGG）在果蝇肝脏类似物和小鼠肝脏中有效激活了Nrf2。这种激活足以防止两种氧化性肝损伤模型，即醋氨酚过量和急性乙醇中毒。通过tandemmass光谱法对LGG治疗小鼠的门脉循环进行表征，确定了LGG产生的Nrf2小分子激活剂5-甲氧基吲哚乙酸。总之，这些数据证明了肠道微生物调节肝脏氧化损伤易感性的机制。

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《Cell metabolism》 |2020年第5期|共18页
作者
Saeedi Bejan J.; Liu Ken H.; Owens Joshua A.; Hunter-Chang Sarah; Camacho Mary C.; Eboka Richard U.; Chandrasekharan Bindu; Baker Nusaiba F.; Darby Trevor M.; Robinson Brian S.; Jones Rheinallt M.; Jones Dean P.; Neish Andrew S.;
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Emory Univ Sch Med Dept Pathol Atlanta GA 30322 USA;

Emory Univ Div Pulm Allergy &

Crit Care Med Dept Med Sch Med Atlanta GA 30322 USA;

Emory Univ Div Pulm Allergy &

Crit Care Med Dept Med Sch Med Atlanta GA 30322 USA;

Emory Univ Sch Med Dept Pathol Atlanta GA 30322 USA;

Emory Univ Sch Med Dept Pathol Atlanta GA 30322 USA;

Emory Univ Sch Med Dept Pathol Atlanta GA 30322 USA;

Emory Univ Sch Med Dept Pathol Atlanta GA 30322 USA;

Emory Univ Sch Med Dept Pathol Atlanta GA 30322 USA;

Emory Univ Sch Med Dept Pediat Div Pediat Gastroenterol Hepatol &

Nutr Atlanta GA 30322 USA;

Emory Univ Sch Med Dept Pathol Atlanta GA 30322 USA;

Emory Univ Sch Med Dept Pediat Div Pediat Gastroenterol Hepatol &

Nutr Atlanta GA 30322 USA;

Emory Univ Div Pulm Allergy &

Crit Care Med Dept Med Sch Med Atlanta GA 30322 USA;

Emory Univ Sch Med Dept Pathol Atlanta GA 30322 USA;

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正文语种 eng
中图分类内分泌腺疾病及代谢病;
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1. Depletion of activated hepatic stellate cell correlates with severe liver damage and abnormal liver regeneration in acetaminophen-induced liver injury [J] . Kuntang Shen, Wenju Chang, Xiaodong Gao, 生物化学与生物物理学报：英文版 . 2011,第004期
2. Depletion of activated hepatic stellate cell correlates with severe liver damage and abnormal liver regeneration in acetaminophen-induced liver injury [J] . Kuntang Shen, Wenju Chang, Xiaodong Gao, 生物化学与生物物理学报：英文版 . 2011,第004期
3. Ethyl ferulate protects against lipopolysaccharide-induced acute lung injury by activating AMPK/Nrf2 signaling pathway [J] . Ya-xian Wu, Jun Zhu, Yong-quan Chen, 中国药理学报：英文版 . 2021,第012期
4. Activation of Nrf2/NQO1 Pathway Attenuates Oxidative Stress in Neuronal Cells Induced by Microwave and Protects Neurite Development [J] . HU Shao Hua, LU Li, WANG Hui, 生物医学与环境科学（英文版） . 2021,第011期
5. Emodin protects rat liver from CCl4-induced fibrogenesis via inhibition of hepatic stellate cells activation [J] . Miao-Xian Dong, Yan Jia, Ying-Bo Zhang, 世界胃肠病学杂志：英文版 . 2009,第038期
6. Polysaccharides from Enteromorpha prolifera protect against carbon tetrachloride-induced acute liver injury in mice via activation of Nrf2/HO-1 signaling, and suppression of oxidative stress, inflammation and apoptosis [J] . Food & Function . 2020,第5期

机译：来自肠球ProLifera的多糖通过激活NRF2 / HO-1信号传导和抑制氧化应激，炎症和细胞凋亡的抗氯化物诱导小鼠中的急性肝损伤。
7. Helenalin from Centipeda minima ameliorates acute hepatic injury by protecting mitochondria function, activating Nrf2 pathway and inhibiting NF-kappa B activation [J] . Li Yan, Zeng Yongmei, Huang Quanfang, Biomedicine & pharmacotherapy =: Biomedecine & pharmacotherapie . 2019,第119期

机译：来自Centipeda Minima的Helenalin通过保护线粒体功能，激活NRF2途径和抑制NF-Kappa B激活来改善急性肝损伤
8. Tropisetron Protects Against Acetaminophen-Induced Liver Injury via Suppressing Hepatic Oxidative Stress and Modulating the Activation of JNK/ERK MAPK Pathways [J] . Fu-Chao Liu, Hung-Chen Lee, Chia-Chih Liao, BioMed research international . 2016,第21期

机译：Tropisetron通过抑制肝氧化应激和调节JNK / ERK MAPK途径的激活来保护乙酰氨基酚诱导的肝损伤
9. Transcription factor Nrf2 regulates adaptive cell responses towards resin monomer-induced oxidative stress through the activation of enzymatic antioxidants [C] . Helmut Schweikl, Christine Petzel, Carola Bolay, World biomaterials congress . 2016

机译：转录因子Nrf2通过酶促抗氧化剂的活化调节对树脂单体诱导的氧化应激的适应性细胞反应
10. The role of Nrf2 in preventing oxidative/electrophilic stress-induced liver injury. [D] . Wu, Kai. 2012

机译：Nrf2在预防氧化/亲电子应激引起的肝损伤中的作用。
11. Tropisetron Protects Against Acetaminophen-Induced Liver Injury via Suppressing Hepatic Oxidative Stress and Modulating the Activation of JNK/ERK MAPK Pathways [O] . Fu-Chao Liu, Hung-Chen Lee, Chia-Chih Liao, 2006

机译：Tropisetron可通过抑制肝氧化应激并调节JNK / ERK MAPK途径的激活来防止对乙酰氨基酚引起的肝损伤。
12. Tropisetron Protects Against Acetaminophen-Induced Liver Injury via Suppressing Hepatic Oxidative Stress and Modulating the Activation of JNK/ERK MAPK Pathways [O] . Fu-Chao Liu, Hung-Chen Lee, Chia-Chih Liao, 2016

机译：Tropisetron通过抑制肝氧化胁迫并调节JNK / ERK MAPK途径的激活来保护乙酰氨基酚诱导的肝损伤
13. Lactobacilli Activate Human Dendritic Cells that Skew T Cells Toward T Helper 1 Polarization [R] . Mohamadzadeh, M. , Olson, S. , Kalina, W. V. , 2005

机译：乳酸杆菌激活人类树突状细胞，使T细胞向T辅助细胞1极化倾斜

Gut-Resident Lactobacilli Activate Hepatic Nrf2 and Protect Against Oxidative Liver Injury

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