Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity (original) (raw)

Nature volume 482, pages 179–185 (2012)Cite this article

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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.

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Data deposits

16S rRNA data sets have been deposited in MG-RAST under accession number qiime:909.

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Acknowledgements

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.

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Author notes

  1. Jorge Henao-Mejia, Eran Elinav and Chengcheng Jin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunobiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA
    Jorge Henao-Mejia, Eran Elinav, Chengcheng Jin, Till Strowig, Christoph A. Thaiss & Richard A. Flavell
  2. Department of Cell Biology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA
    Chengcheng Jin
  3. Department of Pathology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA
    Liming Hao
  4. Department of Internal Medicine, Yale University School of Medicine, New Haven, 06520, Connecticut, USA
    Wajahat Z. Mehal, Michael J. Jurczak, Joao-Paulo Camporez & Gerald I. Shulman
  5. Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, 63108, Missouri, USA
    Andrew L. Kau & Jeffrey I. Gordon
  6. Division of Allergy and Immunology, Department of Internal Medicine, Washington University School of Medicine, St Louis, 63108, Missouri, USA
    Andrew L. Kau
  7. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, 06520, Connecticut, USA
    Stephanie C. Eisenbarth
  8. Howard Hughes Medical Institute, Chevy Chase, 20815, Maryland, USA
    Gerald I. Shulman & Richard A. Flavell
  9. Department of Pediatrics, Rady Children’s Hospital San Diego, University of California at San Diego, La Jolla, 92093, California, USA
    Hal M. Hoffman

Authors

  1. Jorge Henao-Mejia
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  2. Eran Elinav
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  3. Chengcheng Jin
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  4. Liming Hao
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  5. Wajahat Z. Mehal
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  6. Till Strowig
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  7. Christoph A. Thaiss
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  8. Andrew L. Kau
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  9. Stephanie C. Eisenbarth
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  10. Michael J. Jurczak
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  11. Joao-Paulo Camporez
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  12. Gerald I. Shulman
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  13. Jeffrey I. Gordon
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  14. Hal M. Hoffman
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  15. Richard A. Flavell
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Contributions

J.H.-M., E.E. and R.A.F. designed the study and wrote the manuscript. J.H.-M., E.E., C.J., L.H., W.Z.M., M.J.J., J.-P.C., G.I.S. and C.A.T. performed the in vitro and in vivo experimental work and edited the manuscript. T.S. and S.C.E. supported the work with key suggestions and editing of the manuscript. H.M.H. provided the Nlrp3 knock-in mice and provided valuable feedback on the manuscript. A.L.K. and J.I.G. performed the stool processing and metagenomic analysis of the microbiota and provided key suggestions to the manuscript and participated in its editing. R.A.F. directed the project.

Corresponding author

Correspondence toRichard A. Flavell.

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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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Editorial Summary

Using a mouse model, Richard Flavell and co-workers study the inflammatory processes associated with progression from non-alcoholic fatty liver disease — the leading cause of chronic liver disease in developed countries — to the more severe non-alcoholic steatohepatitis, which often leads to cirrhosis and hepatocellular carcinoma. They find that alterations of the intestinal microbiota associated with the NLRP6 and NLRP3 inflammasomes enhance disease in mice with diet-induced non-alcoholic fatty liver syndrome. These findings highlight the pivotal role of the microbiota in the development of autoinflammatory and metabolic disorders, and point to the manipulation of host–microflora interactions as a focus for new therapies.