Lack of NLRP3-inflammasome leads to gut-liver axis derangement, gut dysbiosis and a worsened phenotype in a mouse model of NAFLD

Abstract

Non-Alcoholic Fatty Liver Disease (NAFLD) represents the most common form of chronic liver injury and can progress to cirrhosis and hepatocellular carcinoma. A “multi-hit” theory, involving high fat diet and signals from the gut-liver axis, has been hypothesized. The role of the NLRP3-inflammasome, which senses dangerous signals, is controversial. Nlrp3−/− and wild-type mice were fed a Western-lifestyle diet with fructose in drinking water (HFHC) or a chow diet. Nlrp3−/−-HFHC showed higher hepatic expression of PPAR γ2 (that regulates lipid uptake and storage) and triglyceride content, histological score of liver injury and greater adipose tissue inflammation. In Nlrp3−/−-HFHC, dysregulation of gut immune response with impaired antimicrobial peptides expression, increased intestinal permeability and the occurrence of a dysbiotic microbiota led to bacterial translocation, associated with higher hepatic expression of TLR4 (an LPS receptor) and TLR9 (a receptor for double-stranded bacterial DNA). After antibiotic treatment, gram-negative species and bacterial translocation were reduced, and adverse effects restored both in liver and adipose tissue. In conclusion, the combination of a Western-lifestyle diet with innate immune dysfunction leads to NAFLD progression, mediated at least in part by dysbiosis and bacterial translocation, thus identifying new specific targets for NAFLD therapy.

<p>Gut Dysbiosis and Increased Intestinal Permeability Drive microRNAs, NLRP-3 Inflammasome and Liver Fibrosis in a Nutritional Model of Non-Alcoholic Steatohepatitis in Adult Male Sprague Dawley Rats</p>

“…The integrity of gut epithelium can be disturbed by HFD, leading to the change on gut permeability and then to endotoxemia and systemic inflammation, data that corroborate with our results. 12 , 58 , 59 Below the epithelium, the gut vascular barrier actively controls hematogenous bacterial dissemination via the portal circulation. 57 In the context of NASH, it is unclear if increased intestinal permeability due to disrupted intestinal epithelial barrier alone is sufficient to induce bacteria and lipopolysaccharides (LPS) translocation and drive liver damage, or if gut vascular barrier disruption is also required.…”

“…These patterns are recognized by immune receptors on liver cells such as Kupffer cells and hepatic stellate cells which initiate and maintain inflammatory cascades that ultimately lead to liver damage in the form of fibrosis. 8 , 12 During this process, epigenetic changes also occur, mediated by microRNAs that act in the expression or suppression of genes responsible for the worsening of liver damage. These factors not only drive hepatic inflammation and progressive fibrosis but also contribute to mortality in end-stage liver disease due to their role in secondary infections such as spontaneous bacterial peritonitis and hepatic encephalopathy.…”

“…9 While intestinal permeability is not the primary driver of liver inflammation and fibrosis, it has become evident that the inflammatory response to microbial antigens as a result of increased intestinal permeability strongly influences the progression of disease. 9 , 12 …”

Role of inflammatory response in liver diseases: Therapeutic strategies

“…However and in general terms, this activation is usually proinflammatory in the liver, and its inactivation and absence in relation to the microbiota should be carefully studied. Recently, Pierantonelli et al[ 39 ] have shown that the progression of liver fibrosis is associated with the downregulation of NLRP3 in the gut which, together with the current evidence of a strong correlation between intestinal changes (including modification of microbiota composition) and liver disease, makes the role of NLRP3 in the intestine extremely attractive as a protective factor. Finally, MCC950 has been proven as an effective NLRP3 inhibitor, being able to reduce liver injury and inflammation.…”

Adapted Immune Responses of Myeloid-Derived Cells in Fatty Liver Disease

“…Similarly, in vitro exposure of phagocytes to cholesterol crystals induced assembly of NLRP3 inflammasomes ( 74 ). In contrast, lack of the NLRP3 inflammasome results in decreased levels of IL-18 and other cytokines in the intestine and is related to an altered gut microbiota and derangement of the gut-liver-axis ( 10 , 75 ). Consistently, NLRP3 blockade improved NAFLD in obese mice presumably by inhibiting inflammasome activation mediated by cholesterol crystals in myeloid cells ( 51 ).…”