The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity
Open accessAbstract
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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In the citing paper
“LPS-mediated activation of KCs via TLR4 leading to MyD88-dependent activation of NF-kB, production of proinflammatory cytokines and subsequent liver injury have also been demonstrated for both MASH(214) and ASH(215).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [214]
Experimental — accuracy not yet measuredIn the citing paper
“In NAFLD models, lack of inflammasomes has been demonstrated to select a pathogenetic microbiota which was associated with a more severe degree of liver injury [226].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [226]
In the citing paper
“Either in patients with NASH or animal models, the expression of inflammasome components was increased, indicating the potential role in the pathogenesis of liver injury [226,227,288,289,290,291].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [226]
In the citing paper
“These results indicate that complex interactions between the diet, the innate immunity, bacteria and intestinal function occurs in the development of NASH [226,227], and similar observations were obtained in experimental models of HCC development [285,286,287].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [226]
In the citing paper
“Animal studies have demonstrated a direct role of altered intestinal microbiota in steatosis,15 NASH(16), fibrosis17 and liver cancer.18”
From Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling (2023) · cites this paper as [16]
In the citing paper
“Co-housing wildtype mice with mice prone to MASH led to increased disease severity in wildtype mice, presumably due to a transfer of fecal microbiota (204).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [204]
In the citing paper
“In the MCD diet model, the microbiota has a key role in NASH exacerbation as demonstrated by experiments, in which co-housing transmitted NASH risk and antibiotics reduced NASH risk65.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [65]
In the citing paper
“Functional studies utilizing co-housing and faecal transplantation have provided evidence that dysbiosis is a transmissible driver of liver disease development and progression 65,89.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [65]
In the citing paper
“Similarly, dysbiosis represented a transmissible risk factor in a genetic NASH model in which NASH was triggered by inflammasome deficiency; co-housing of dysbiotic inflammasome-deficient mice with control mice resulted in the development of NASH in control mice65.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [65]
In the citing paper
“Association of bacterial composition with many diseases has been observed, including immune, inflammatory, and metabolic phenotypes.”
From The Gut Microbiome Contributes to a Substantial Proportion of the Variation in Blood Lipids (2015) · cites this paper as [5]
In the citing paper
“Disruption of the murine inflammasomes (see box 1) is associated with an increase in Bacteroidetes and reduction in Firmicutes and results in severe hepatic steatosis and inflammation.41”
From The gut microbiota and host health: a new clinical frontier (2016) · cites this paper as [41]
In the citing paper
“the NLRP6 and NLRP3 inflammasomes may exert protective effects against NAFLD/NASH through modulation of the gut microbiota.181”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [181]
In the citing paper
“Dysbiosis has been observed in mice deficient for inflammasomes components, including NLRP6, ASC, caspase-1, and IL-18 [131,132,133,134].”
From Gut Microbiota and Cancer: From Pathogenesis to Therapy (2019) · cites this paper as [134]
In the citing paper
“The Muc2-KO mouse possesses a distinct gut-associated bacterial community that is influenced by its altered genetic and immune states, as has been shown in other genetic knockout mouse models.4,53–55”
From Using Corticosteroids to Reshape the Gut Microbiome: Implications for Inflammatory Bowel Diseases (2015) · cites this paper as [54]
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Metadata
- Authors
- Henao-Mejia, J., Elinav, E., Jin, C., Hao, L., Mehal, W. Z., Strowig, T., Thaiss, C. A., Kau, A. L., Eisenbarth, S. C., Jurczak, M. J., Camporez, J.-P., Shulman, G. I., Gordon, J. I., Hoffman, H. M., & Flavell, R. A.
- Affiliations
- Yale University (US)
- Washington University in St. Louis (US)
- Howard Hughes Medical Institute (US)
- University of California San Diego (US)
- Corresponding author
- Flavell, Richard A.
- ORCID
- Venue
- Nature
- Published
- 2012-02
- Volume
- 482
- Issue
- 7384
- Pages
- 179-185
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3276682
- OpenAlex
- W2144275312
- Cited by
- 2,435
- References
- 41
- Citations by year
- 2026: 83 · 2025: 103 · 2024: 137 · 2023: 165 · 2022: 158 · 2021: 182 · 2020: 215 · 2019: 188 · 2018: 197 · 2017: 184 · 2016: 172 · 2015: 195 · 2014: 181 · 2013: 185 · 2012: 85
- FWCI
- 154.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Crohn's and Colitis Foundation
- U.S. Public Health Service (K08A1085038)
- National Heart, Lung, and Blood Institute (T32HL007974)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, R01DK040936, U24DK059635, R01DK076674, R24DK085638, P30DK045735)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, NLRP3 inflammasome, NLRP6 inflammasome, IL-18, gut dysbiosis, metabolic syndrome, obesity, hepatic steatosis, liver inflammation, TLR4, TLR9, TNF-α, Porphyromonadaceae, host-microbiota interactions, autoinflammatory disease
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Carrier Proteins, Choline, Colon, Cytoskeletal Proteins, Disease Models, Animal, Fatty Liver, Inflammation, Male, Methionine, Mice, Inbred C57BL, Obesity, Receptors, Cell Surface, RNA, Ribosomal, 16S, Tumor Necrosis Factor-alpha, Disease Progression, Interleukin-18, Apoptosis Regulatory Proteins, Toll-Like Receptor 4, Toll-Like Receptor 9, Mice, CARD Signaling Adaptor Proteins, Metagenome, Inflammasomes, Non-alcoholic Fatty Liver Disease
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