Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity

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

Research output: Contribution to journalArticle

1263 Scopus citations

Abstract

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 inflammasome-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.

Original languageEnglish
Pages (from-to)179-185
Number of pages7
JournalNature
Volume482
Issue number7384
DOIs
StatePublished - Feb 9 2012

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    Henao-Mejia, J., Elinav, E., Jin, C., Hao, L., Mehal, W. Z., Strowig, T., Thaiss, C. A., Kau, A. L., Eisenbarth, S. C., Jurczak, M. J., Camporez, J. P., Shulman, G. I., Gordon, J. I., Hoffman, H. M., & Flavell, R. A. (2012). Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature, 482(7384), 179-185. https://doi.org/10.1038/nature10809