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Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity

机译：炎性体介导的营养不良调节NAFLD和肥胖的发展

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摘要

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty per cent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet the causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different mouse models reveal that inflammasome-deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic tumour-necrosis factor (TNF)-α expression that drives NASH progression. Furthermore, co-housing of iriflammasome-deficient mice with wild-type mice results in exacerbation of hepatic steatosis and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders.
机译：非酒精性脂肪性肝病（NAFLD）是代谢综合征的肝病表现，也是西方世界慢性肝病的主要原因。 NAFLD个体中有20％会发展出与肝硬化，门脉高压和肝细胞癌相关的慢性肝炎（非酒精性脂肪性肝炎，NASH），但从NAFLD演变为NASH的原因仍然不清楚。在这里，我们显示NLRP6和NLRP3炎性小体以及效应蛋白IL-18会通过调节肠道菌群对NAFLD / NASH进程以及代谢综合征的多个方面产生负面影响。不同的小鼠模型显示，肠道菌群结构中与炎性体缺乏症相关的变化与TLR4和TLR9激动剂流入门脉循环并加剧肝脂肪变性和炎症有关，从而导致肝肿瘤坏死因子（TNF）-驱动NASH进展的α表达。此外，虹膜小体缺陷型小鼠与野生型小鼠的共栖导致肝脂肪变性和肥胖症恶化。因此，由缺陷的NLRP3和NLRP6炎性体感测产生的肠道微生物群与宿主之间的相互作用发生改变，可能会控制多种代谢综合征相关异常的进展速度，从而突出了微生物群在迄今为止似乎无关的全身性疾病的发病机制中的核心作用。自发性和代谢性疾病。

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  • 来源
    《Nature》 |2012年第7384期|p.179-185|共7页
  • 作者

    Jorge Henao-Mejia; Eran Elinav; Chengcheng Jin; Liming Hao; Wajahat Z. Mehal; Till Strowig; Christoph A. Thaiss; Andrew L. Kau; Stephanie C. Eisenbarth; Michael J. Jurczak; Joao-Paulo Camporez; Gerald I. Shulman; Jeffrey I. Gordon; Hal M. Hoffman; Richard A. Flavell;

  • 作者单位

    Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA,Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, Missouri 63108, USA,Division of Allergy and Immunology, Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri 63108, USA;

    Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA;

    Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA,Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA;

    Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, Missouri 63108, USA;

    Department of Pediatrics, Rady Children's Hospital San Diego, University of California at San Diego, LaJolla, California 92093, USA;

    Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA,Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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