title: Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation.
abstract: Gut microbiota is involved in obesity, metabolic syndrome and the progression of nonalcoholic fatty liver disease (NAFLD). It has been recently suggested that the flavonoid quercetin may have the ability to modulate the intestinal microbiota composition, suggesting a prebiotic capacity which highlights a great therapeutic potential in NAFLD. The present study aims to investigate benefits of experimental treatment with quercetin on gut microbial balance and related gut-liver axis activation in a nutritional animal model of NAFLD associated to obesity. C57BL/6J mice were challenged with high fat diet (HFD) supplemented or not with quercetin for 16 weeks. HFD induced obesity, metabolic syndrome and the development of hepatic steatosis as main hepatic histological finding. Increased accumulation of intrahepatic lipids was associated with altered gene expression related to lipid metabolism, as a result of deregulation of their major modulators. Quercetin supplementation decreased insulin resistance and NAFLD activity score, by reducing the intrahepatic lipid accumulation through its ability to modulate lipid metabolism gene expression, cytochrome P450 2E1 (CYP2E1)-dependent lipoperoxidation and related lipotoxicity. Microbiota composition was determined via 16S ribosomal RNA Illumina next-generation sequencing. Metagenomic studies revealed HFD-dependent differences at phylum, class and genus levels leading to dysbiosis, characterized by an increase in Firmicutes/Bacteroidetes ratio and in Gram-negative bacteria, and a dramatically increased detection of Helicobacter genus. Dysbiosis was accompanied by endotoxemia, intestinal barrier dysfunction and gut-liver axis alteration and subsequent inflammatory gene overexpression. Dysbiosis-mediated toll-like receptor 4 (TLR-4)-NF-κB signaling pathway activation was associated with inflammasome initiation response and reticulum stress pathway induction. Quercetin reverted gut microbiota imbalance and related endotoxemia-mediated TLR-4 pathway induction, with subsequent inhibition of inflammasome response and reticulum stress pathway activation, leading to the blockage of lipid metabolism gene expression deregulation. Our results support the suitability of quercetin as a therapeutic approach for obesity-associated NAFLD via its anti-inflammatory, antioxidant and prebiotic integrative response.
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain. Electronic address: dporrs00@estudiantes.unileon.es.
authors.forename: David
authors.initials: D
authors.lastname: Porras
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain. Electronic address: esthernistal@hotmail.com.
authors.forename: Esther
authors.initials: E
authors.lastname: Nistal
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain. Electronic address: smarf@unileon.es.
authors.forename: Susana
authors.initials: S
authors.lastname: Martínez-Flórez
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain. Electronic address: spisv@unileon.es.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pisonero-Vaquero
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Department of Gastroenterology, Complejo Asistencial Universitario de León, León, Spain. Electronic address: jolcozg@gmail.com.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Olcoz
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain; Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain. Electronic address: ramiro.jover@uv.es.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Jover
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: jgonga@unileon.es.
authors.forename: Javier
authors.initials: J
authors.lastname: González-Gallego
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: mvgarm@unileon.es.
authors.forename: María Victoria
authors.initials: MV
authors.lastname: García-Mediavilla
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: ssanc@unileon.es.
authors.forename: Sonia
authors.initials: S
authors.lastname: Sánchez-Campos
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D000069196:Gastrointestinal Microbiome / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D007422:Intestines / Q000382:microbiology; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D011794:Quercetin / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D011794:Quercetin
keywords: CYP2E1; Dysbiosis; Endoplasmic reticulum stress; Gut-liver axis; Inflammasome; Inflammation; Intestinal barrier function; Intestinal microbiota; Lipid metabolism; Lipotoxicity; NAFLD; Quercetin