Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages.
Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages.
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肠道菌群衍生的色氨酸代谢产物调节肝细胞和巨噬细胞中的炎症反应。
DOI：
10.1016/j.celrep.2018.03.109
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发表时间：
2018-04-24
期刊：
影响因子：
8.8
通讯作者：
Lee K
中科院分区：
文献类型：
--
作者：
Krishnan S;Ding Y;Saedi N;Choi M;Sridharan GV;Sherr DH;Yarmush ML;Alaniz RC;Jayaraman A;Lee K
肠道微生物区系在脂肪性肝病的发展中起着重要作用，然而，其介体及其机制仍有待阐明。比较无菌小鼠和常规饲养小鼠之间的代谢物谱差异，以及喂低脂和高脂饮食(HFD)的小鼠之间的差异，我们确定色胺和吲哚-3-乙酸酯(I3A)是依赖于微生物区系并在HFD下耗尽的代谢物。这两种代谢物都减少了脂肪酸和内毒素刺激的巨噬细胞中促炎细胞因子的产生，并抑制了细胞向趋化因子的迁移，其中I3A显示出更强的效力。在肝细胞中，I3A减轻了脂质负荷下的炎症反应，并减少了脂肪酸合成酶和固醇调节元件结合蛋白-1c的表达。这些作用在芳香烃受体(AhR)拮抗剂存在下被取消，表明这些作用是依赖于AhR的。我们的结果表明，肠道微生物区系可能通过代谢产物与宿主受体结合来影响肝脏的炎症反应。肠道微生物区系失调是导致脂肪肝疾病进展的一个新因素。Krishnan等人。利用代谢组学和生化分析，结合动物和细胞培养模型，识别与宿主受体结合的微生物区系依赖的代谢物，以影响脂质负荷下的肝脏炎症反应。
The gut microbiota plays a significant role in the progression of fatty liver disease; however, the mediators and their mechanisms remain to be elucidated. Comparing metabolite profile differences between germ-free and conventionally raised mice against differences between mice fed a low- and high-fat diet (HFD), we identified tryptamine and indole-3-acetate (I3A) as metabolites that depend on the microbiota and are depleted under a HFD. Both metabolites reduced fatty-acid- and LPS-stimulated production of pro-inflammatory cytokines in macrophages and inhibited the migration of cells toward a chemokine, with I3A exhibiting greater potency. In hepatocytes, I3A attenuated inflammatory responses under lipid loading and reduced the expression of fatty acid synthase and sterol regulatory element-binding protein-1c. These effects were abrogated in the presence of an aryl-hydrocarbon receptor (AhR) antagonist, indicating that the effects are AhR dependent. Our results suggest that gut microbiota could influence inflammatory responses in the liver through metabolites engaging host receptors. Dysbiosis of the intestinal microbiota is an emerging factor contributing to the progression of fatty liver disease. Krishnan et al. utilize metabolomics and biochemical assays in conjunction with animal and cell culture models to identify microbiota-dependent metabolites that engage a host receptor to affect liver inflammatory responses under lipid loading.
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DOI：
10.1097/mco.0000000000000209
发表时间：
2015-09
影响因子：
3.1
作者：
Murphy EA;Velazquez KT;Herbert KM
通讯作者：
Herbert KM
影响因子：
3.7
作者：
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影响因子：
4.6
作者：
Hubbard TD;Murray IA;Bisson WH;Lahoti TS;Gowda K;Amin SG;Patterson AD;Perdew GH
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Perdew GH
影响因子：
14.9
作者：
Allen F;Pon A;Wilson M;Greiner R;Wishart D
通讯作者：
Wishart D
影响因子：
9.8
作者：
Buzzetti, Elena;Pinzani, Massimo;Tsochatzis, Emmanuel A.
通讯作者：
Tsochatzis, Emmanuel A.