Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Increased severity of NASH in inflammasome-deficient mice.
Figure 2: Increased severity of NASH in Asc- and Il18 -deficient mice is transmissible to co-housed wild-type animals.
Figure 3: 16S rRNA sequencing demonstrates diet and co-housing associated changes in gut microbial ecology.
Figure 4: Increased severity of NASH in Asc -deficient and co-housed wild-type animals is mediated by TLR4, TLR9 and TNF-α.
Figure 5: Increased severity of NASH in Asc -deficient mice is transmissible to db/db by co-housing and is mediated by CCL5-induced intestinal inflammation.
Figure 6: Asc -deficient mice develop increased obesity and loss of glycaemic control on HFD.

Similar content being viewed by others

Accession codes

Data deposits

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

References

  1. Sheth, S. G., Gordon, F. D. & Chopra, S. Nonalcoholic steatohepatitis. Ann. Intern. Med. 126, 137–145 (1997)

    Article  CAS  Google Scholar 

  2. Ludwig, J., Viggiano, T. R., McGill, D. B. & Oh, B. J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin. Proc. 55, 434–438 (1980)

    CAS  PubMed  Google Scholar 

  3. Marchesini, G. et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37, 917–923 (2003)

    Article  Google Scholar 

  4. Caldwell, S. H. et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 29, 664–669 (1999)

    Article  CAS  Google Scholar 

  5. Shimada, M. et al. Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J. Hepatol. 37, 154–160 (2002)

    Article  Google Scholar 

  6. Propst, A., Propst, T., Judmaier, G. & Vogel, W. Prognosis in nonalcoholic steatohepatitis. Gastroenterology 108, 1607 (1995)

    Article  CAS  Google Scholar 

  7. Charlton, M. Cirrhosis and liver failure in nonalcoholic fatty liver disease: molehill or mountain? Hepatology 47, 1431–1433 (2008)

    Article  Google Scholar 

  8. Hjelkrem, M. C., Torres, D. M. & Harrison, S. A. Nonalcoholic fatty liver disease. Minerva Med. 99, 583–593 (2008)

    CAS  PubMed  Google Scholar 

  9. Day, C. P. & James, O. F. Steatohepatitis: a tale of two “hits”? Gastroenterology 114, 842–845 (1998)

    Article  CAS  Google Scholar 

  10. Sanyal, A. J. et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120, 1183–1192 (2001)

    Article  CAS  Google Scholar 

  11. Sutterwala, F. S., Ogura, Y. & Flavell, R. A. The inflammasome in pathogen recognition and inflammation. J. Leukoc. Biol. 82, 259–264 (2007)

    Article  CAS  Google Scholar 

  12. Martinon, F., Burns, K. & Tschopp, J. The inflammasome. Mol. Cell 10, 417–426 (2002)

    Article  CAS  Google Scholar 

  13. Agostini, L. et al. NALP3 forms an IL-1β-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20, 319–325 (2004)

    Article  CAS  Google Scholar 

  14. Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011)

    Article  CAS  ADS  Google Scholar 

  15. Varela-Rey, M. et al. Non-alcoholic steatohepatitis and animal models: understanding the human disease. Int. J. Biochem. Cell Biol. 41, 969–976 (2009)

    Article  CAS  Google Scholar 

  16. Brydges, S. D. et al. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity 30, 875–887 (2009)

    Article  CAS  Google Scholar 

  17. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011)

    Article  CAS  Google Scholar 

  18. Rivera, C. A. et al. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J. Hepatol. 47, 571–579 (2007)

    Article  CAS  Google Scholar 

  19. Miura, K. et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1β in mice. Gastroenterology 139, 323–334 e7. (2010)

    Article  Google Scholar 

  20. Seki, E. et al. TLR4 enhances TGF-β signaling and hepatic fibrosis. Nature Med. 13, 1324–1332 (2007)

    Article  CAS  Google Scholar 

  21. Crespo, J. et al. Gene expression of tumor necrosis factor α and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 34, 1158–1163 (2001)

    Article  CAS  Google Scholar 

  22. Li, Z. et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 37, 343–350 (2003)

    Article  CAS  ADS  Google Scholar 

  23. Diehl, A. M. Lessons from animal models of NASH. Hepatol. Res. 33, 138–144 (2005)

    Article  CAS  Google Scholar 

  24. Broomé, U., Glaumann, H. & Hultcrantz, R. Liver histology and follow up of 68 patients with ulcerative colitis and normal liver function tests. Gut 31, 468–472 (1990)

    Article  Google Scholar 

  25. Guo, X. et al. Leptin signaling in intestinal epithelium mediates resistance to enteric infection by Entamoeba histolytica. Mucosal Immunol. 4, 294–303 (2011)

    Article  CAS  Google Scholar 

  26. Ikejima, K. et al. The role of leptin in progression of non-alcoholic fatty liver disease. Hepatol. Res. 33, 151–154 (2005)

    Article  CAS  Google Scholar 

  27. Guebre-Xabier, M. et al. Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: potential mechanism for sensitization to liver damage. Hepatology 31, 633–640 (2000)

    Article  CAS  Google Scholar 

  28. Almeida, J., Galhenage, S., Yu, J., Kurtovic, J. & Riordan, S. M. Gut flora and bacterial translocation in chronic liver disease. World J. Gastroenterol. 12, 1493–1502 (2006)

    Article  Google Scholar 

  29. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature Med. 17, 179–188 (2011)

    Article  CAS  Google Scholar 

  30. Wen, H. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nature Immunol. 12, 408–415 (2011)

    Article  CAS  Google Scholar 

  31. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010)

    Article  CAS  ADS  Google Scholar 

  32. Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nature Immunol. 11, 136–140 (2010)

    Article  CAS  Google Scholar 

  33. Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nature Immunol. 11, 897–904 (2010)

    Article  CAS  Google Scholar 

  34. Stienstra, R. et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc. Natl Acad. Sci. USA 108, 15324–15329 (2011)

    Article  CAS  ADS  Google Scholar 

  35. Netea, M. G. et al. Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nature Med. 12, 650–656 (2006)

    Article  CAS  Google Scholar 

  36. Bajaj, J. S. et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am. J. Physiol. Gastrointest. Liver Physiol. 302, 168–175 (2011)

    Article  Google Scholar 

  37. Makiura, N. et al. Relationship of Porphyromonas gingivalis with glycemic level in patients with type 2 diabetes following periodontal treatment. Oral Microbiol. Immunol. 23, 348–351 (2008)

    Article  CAS  Google Scholar 

  38. Sutterwala, F. S. et al. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24, 317–327 (2006)

    Article  CAS  Google Scholar 

  39. Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000)

    Article  CAS  ADS  Google Scholar 

  40. Kleiner, D. E. et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41, 1313–1321 (2005)

    Article  Google Scholar 

  41. Caporaso, J. G. et al. QIIME allows analysis of high-throughput community sequencing data. Nature Methods 7, 335–336 (2010)

    Article  CAS  Google Scholar 

Download references

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.

Author information

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
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eran Elinav
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chengcheng Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liming Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wajahat Z. Mehal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Till Strowig
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christoph A. Thaiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andrew L. Kau
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stephanie C. Eisenbarth
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michael J. Jurczak
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Joao-Paulo Camporez
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Gerald I. Shulman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jeffrey I. Gordon
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hal M. Hoffman
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Richard A. Flavell
    View author publications

    You can also search for this author in PubMed Google Scholar

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 to Richard A. Flavell.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-12 with legends. (PDF 1803 kb)

Supplementary Tables

This file contains Supplementary Tables 1-3. (PDF 279 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10809

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing