title: CX3CR1 is a gatekeeper for intestinal barrier integrity in mice: Limiting steatohepatitis by maintaining intestinal homeostasis.
abstract: Nonalcoholic fatty liver disease is seen as the hepatic manifestation of the metabolic syndrome and represents the most common liver disease in Western societies. The G protein-coupled chemokine receptor CX3CR1 plays a central role in several metabolic syndrome-related disease manifestations and is involved in maintaining intestinal homeostasis. Because diet-induced intestinal dysbiosis is a driver for nonalcoholic fatty liver disease, we hypothesized that CX3CR1 may influence the development of steatohepatitis. In two independent models of diet-induced steatohepatitis (high-fat diet and methionine/choline-deficient diet), CX3CR1 protected mice from excessive hepatic steatosis and inflammation, as well as systemic glucose intolerance. Lack of Cx3cr1 expression was associated with significantly altered intestinal microbiota composition, which was linked to an impaired intestinal barrier. Concomitantly, endotoxin levels in portal serum and inflammatory macrophages in liver were increased in Cx3cr1-/- mice, indicating an increased inflammatory response. Depletion of intestinal microbiota by administration of broad-spectrum antibiotics suppressed the number of infiltrating macrophages and promoted macrophage polarization in liver. Consequently, antibiotic-treated mice demonstrated a marked improvement of steatohepatitis.
  
  
  CONCLUSIONS
  Microbiota-mediated activation of the innate immune responses through CX3CR1 is crucial for controlling steatohepatitis progression, which recognizes CX3CR1 as an essential gatekeeper in this scenario.
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Kai Markus
authors.initials: KM
authors.lastname: Schneider
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Veerle
authors.initials: V
authors.lastname: Bieghs
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Heymann
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Institute of Pharmacology and Toxicology, Medical Faculty, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dreymueller
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Lijun
authors.initials: L
authors.lastname: Liao
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Mick
authors.initials: M
authors.lastname: Frissen
authors.affiliation: Institute of Pharmacology and Toxicology, Medical Faculty, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
authors.affiliation: Institute of Pathology, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.affiliation: Institute of Molecular Medicine, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Pabst
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany.|Department of Medicine, University of Massachusetts Medical School, Worcester, MA.|German Center for Neurodegenerative Diseases, Bonn, Germany.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Sellge
authors.affiliation: Department of Medical Microbiology, School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: John
authors.initials: J
authors.lastname: Penders
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018988:Bacterial Translocation; D001786:Blood Glucose / Q000032:analysis; D000073883:CX3C Chemokine Receptor 1; D006706:Homeostasis; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000382:microbiology; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota; D065626:Non-alcoholic Fatty Liver Disease / Q000276:immunology* / Q000378:metabolism; D019707:Receptors, Chemokine / Q000502:physiology*
chemical_list: D000900:Anti-Bacterial Agents; D001786:Blood Glucose; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine