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.
Lack of NLRP3-inflammasome leads to gut-liver axis derangement, gut dysbiosis and a worsened phenotype in a mouse model of NAFLD / Pierantonelli, Irene; Rychlicki, Chiara; Agostinelli, Laura; Giordano, DEBORA MARIA; Gaggini, Melania; Fraumene, Cristina; Saponaro, Chiara; Manghina, Valeria; Sartini, Loris; Mingarelli, Eleonora; Pinto, Claudio; Buzzigoli, Emma; Trozzi, Luciano; Giordano, Antonio; Marzioni, Marco; DE MINICIS, Samuele; Uzzau, Sergio; Cinti, Saverio; Gastaldelli, Amalia; SVEGLIATI BARONI, Gianluca. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - ELETTRONICO. - 7:(2017), p. 17568. [10.1038/s41598-017-17187-3]