Inflammasome-mediated Dysbiosis Regulates Progression of NAFLD and Obesity

Nature. 2012 Feb 1;482(7384):179-85. doi: 10.1038/nature10809.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / metabolism
  • Choline
  • Colon / microbiology
  • Cytoskeletal Proteins / deficiency
  • Disease Models, Animal
  • Disease Progression*
  • Fatty Liver / genetics
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology*
  • Inflammasomes / metabolism*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interleukin-18 / deficiency
  • Male
  • Metagenome
  • Methionine / deficiency
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Non-alcoholic Fatty Liver Disease
  • Obesity / metabolism*
  • Obesity / pathology*
  • RNA, Ribosomal, 16S / genetics
  • Receptors, Cell Surface / metabolism
  • Toll-Like Receptor 4 / deficiency
  • Toll-Like Receptor 4 / metabolism
  • Toll-Like Receptor 9 / deficiency
  • Toll-Like Receptor 9 / metabolism
  • Tumor Necrosis Factor-alpha / deficiency
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Inflammasomes
  • Interleukin-18
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Nod-like receptor pyrin domain-containing protein 6, mouse
  • Pycard protein, mouse
  • RNA, Ribosomal, 16S
  • Receptors, Cell Surface
  • Tlr4 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9
  • Tumor Necrosis Factor-alpha
  • Methionine
  • Choline