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.
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16S rRNA data sets have been deposited in MG-RAST under accession number qiime:909.
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We thank E. Eynon, J. Alderman, A. Williams, F. Manzo and H. Elinav for technical assistance and discussions; M. Graham and C. Rahner for performing electron microscopy; D. R. Peaper for assistance in microbiological culture procedures; R. Sherwin for helpful advice; X. Fan for technical assistance; Yale Diabetes Endocrinology Research Center and Mouse Metabolic Phenotyping Center for assistance with the metabolic analysis. E.E. is supported by the Cancer Research Institute (2010-2012) and by a supplementary grant from the Israel-US educational foundation (2009) and is a recipient of the Claire and Emmanuel G. Rosenblatt award from the American Physicians for Medicine in Israel Foundation (2010-2011). J.H.M. and T.S. are supported by Leukemia and Lymphoma Society Postdoctoral Fellowships. S.C.E. is supported by T32HL007974 and K08A1085038. W.Z.M. is supported by R01DK076674-01 and the VA Merit award. This work was supported in part by the Howard Hughes Medical Institute (G.I.S., R.A.F.), the United States-Israel binational Foundation grant (E.E. and R.A.F.), the Crohn’s and Colitis Foundation of America (A.K. and J.I.G.) and R01 DK-40936, R24 DK-085638, P30 DK-45735 and U24 DK-059635 The authors report no conflict of interest.
The authors declare no competing financial interests.
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Henao-Mejia, J., Elinav, E., Jin, C. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012). https://doi.org/10.1038/nature10809
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