Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity.

Content Provider	Europe PMC
Author	Henao-Mejia, Jorge Elinav, Eran Jin, Cheng-Cheng Hao, Liming Mehal, Wajahat Z. Strowig, Till Thaiss, Christoph A. Kau, Andrew L. Eisenbarth, Stephanie C. Jurczak, Michael J. Camporez, Joao-Paulo Shulman, Gerald I. Gordon, Jeffrey I. Hoffman, Hal M. Flavell, Richard A.
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 percent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet 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 animal 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 TNF-α expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient animals to wild type mice results in exacerbation of hepatic steatosis, glucose intolerance, 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.
ISSN	00280836
Volume Number	482
PubMed Central reference number	PMC3276682
Issue Number	7384
PubMed reference number	22297845
Journal	Nature
e-ISSN	14764687
DOI	10.1038/nature10809
Language	English
Publisher Date	2012-02-01
Access Restriction	Open
Rights License	Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
Subject Keyword	Inflammasome non-alcoholic fatty liver disease gut microbiota
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary