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Gut-Resident Lactobacilli Activate Hepatic Nrf2 and Protect Against Oxidative Liver Injury.
Cell Metabolism ( IF 27.7 ) Pub Date : 2020-03-25 , DOI: 10.1016/j.cmet.2020.03.006 Bejan J Saeedi 1 , Ken H Liu 2 , Joshua A Owens 2 , Sarah Hunter-Chang 1 , Mary C Camacho 1 , Richard U Eboka 1 , Bindu Chandrasekharan 1 , Nusaiba F Baker 1 , Trevor M Darby 3 , Brian S Robinson 1 , Rheinallt M Jones 3 , Dean P Jones 2 , Andrew S Neish 1
Cell Metabolism ( IF 27.7 ) Pub Date : 2020-03-25 , DOI: 10.1016/j.cmet.2020.03.006 Bejan J Saeedi 1 , Ken H Liu 2 , Joshua A Owens 2 , Sarah Hunter-Chang 1 , Mary C Camacho 1 , Richard U Eboka 1 , Bindu Chandrasekharan 1 , Nusaiba F Baker 1 , Trevor M Darby 3 , Brian S Robinson 1 , Rheinallt M Jones 3 , Dean P Jones 2 , Andrew S Neish 1
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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 tandem mass 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.
中文翻译：
肠道驻留乳酸杆菌激活肝脏 Nrf2 并防止氧化性肝损伤。
许多研究表明肠道驻留微生物（“肠道微生物组”）在调节宿主健康方面发挥着作用。然而，它们影响全身生理学的机制仍然很大程度上未知。在这项研究中，无菌和常规小鼠肝脏的代谢组学和转录分析揭示了微生物组丰富的动物中 Nrf2 抗氧化剂和外源性反应的上调。使用基于果蝇的筛选测定，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) 有效激活了果蝇肝脏类似物和小鼠肝脏中的 Nrf2。这种激活足以预防两种氧化性肝损伤模型：对乙酰氨基酚过量和急性乙醇中毒。通过串联质谱法对 LGG 处理的小鼠的门脉循环进行表征，鉴定出 LGG 产生的 Nrf2 小分子激活剂 5-甲氧基吲哚乙酸。综上所述，这些数据证明了肠道微生物调节肝脏对氧化损伤的敏感性的机制。
更新日期：2020-03-25
中文翻译：
肠道驻留乳酸杆菌激活肝脏 Nrf2 并防止氧化性肝损伤。
许多研究表明肠道驻留微生物（“肠道微生物组”）在调节宿主健康方面发挥着作用。然而，它们影响全身生理学的机制仍然很大程度上未知。在这项研究中，无菌和常规小鼠肝脏的代谢组学和转录分析揭示了微生物组丰富的动物中 Nrf2 抗氧化剂和外源性反应的上调。使用基于果蝇的筛选测定，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) 有效激活了果蝇肝脏类似物和小鼠肝脏中的 Nrf2。这种激活足以预防两种氧化性肝损伤模型：对乙酰氨基酚过量和急性乙醇中毒。通过串联质谱法对 LGG 处理的小鼠的门脉循环进行表征，鉴定出 LGG 产生的 Nrf2 小分子激活剂 5-甲氧基吲哚乙酸。综上所述，这些数据证明了肠道微生物调节肝脏对氧化损伤的敏感性的机制。
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