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 and Richard A. Flavell ()
Additional contact information
Jorge Henao-Mejia: Yale University School of Medicine
Eran Elinav: Yale University School of Medicine
Chengcheng Jin: Yale University School of Medicine
Liming Hao: Yale University School of Medicine
Wajahat Z. Mehal: Yale University School of Medicine
Till Strowig: Yale University School of Medicine
Christoph A. Thaiss: Yale University School of Medicine
Andrew L. Kau: Center for Genome Sciences and Systems Biology, Washington University School of Medicine
Stephanie C. Eisenbarth: Yale University School of Medicine
Michael J. Jurczak: Yale University School of Medicine
Joao-Paulo Camporez: Yale University School of Medicine
Gerald I. Shulman: Yale University School of Medicine
Jeffrey I. Gordon: Center for Genome Sciences and Systems Biology, Washington University School of Medicine
Hal M. Hoffman: Rady Children’s Hospital San Diego, University of California at San Diego
Richard A. Flavell: Yale University School of Medicine

Nature, 2012, vol. 482, issue 7384, 179-185

Abstract: 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.

Date: 2012
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DOI: 10.1038/nature10809

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