Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity

By Jorge Henao-Mejia, Eran Elinav, C. Jin, L. Hao, W. Mehal, T. Strowig, Christoph A. Thaiss, A. Kau, S. Eisenbarth, M. Jurczak and 5 more. Nature, 2012

2,335 citations recorded by the source corpus.

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.

Subfields: Endocrinology, Diabetes and Metabolism, Epidemiology, Genetics

View Paper: https://www.semanticscholar.org/paper/55c27c9e12864231c0a69ed236ff27237ac85344

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Endocrinology, Diabetes and Metabolism

1. G. Svegliati-Baroni
2. M. Karin
3. F. Marra

In Epidemiology

1. P. Scherer
2. G. Svegliati-Baroni
3. M. Karin
4. Ruth E. Ley
5. Lan Lin
6. Martin J. Blaser
7. R. Flavell
8. A. Diehl

In Genetics

1. Eran Segal
2. M. Karin
3. Ruth E. Ley
4. Kate Schroder
5. Lan Lin
6. Andrew G. Clark
7. Dirk Gevers
8. A. Alekseyenko

Citations in the corpus

• The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation (2016, background): “NLRP3 was first shown to be associated with hereditary autoinflammatory syndromes called cryopyrin-associated periodic syndromes, which are characterized by skin rashes and episodes of fever (Hoffman et al., 2001).”
• Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling (2015, methodology): “…microbiota in multiple mouse models harbors dominance, upon fecal transfer, over a previously stable wild-type (WT) microbiota, leading to transferable disease susceptibility (Couturier-Maillard et al., 2013; Elinav et al., 2011; Garrett et al., 2007; Henao-Mejia et al., 2012; Ivanov et al., 2009).”
• Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients. (2015, neutral): “06), more severe liver injury and higher IR: steatosis (median [IQR]: 60% [30-80] vs.”
• Role of intestinal microbiota and metabolites on gut homeostasis and human diseases (2017, background): “NASH [168, 169], which underpins the involvement of gut microbiota in the metabolic and immunologic aspects of human health.”
• NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. (2014, neutral): “…(mediating mucus barrier defects through NLRP6 inflammasome deficiency), jointly drive compound ‘‘multifactorial’’ phenotypes such as colonic auto-inflammation, nonalcoholic steatohepatitis (NASH), and inflammation-induced cancer (Chen et al., 2011; Henao-Mejia et al., 2012; Normand et al., 2011).”
• Linking Gut Microbiota and Inflammation to Obesity and Insulin Resistance. (2016, background): “Obese and overweight subjects and obese mice have reduced prevalence of Firmicutes and enhanced prevalence of Bacteroidetes (6, 23, 25, 46, 98).”
• Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease (2018, background): “Several evidences in literature demonstrated that the inflammasome activity drives NASH progression, and the inhibition of its activation may improve NAFLD pathology and fibrosis [87, 88].”