title: Lipocalin 2 Protects from Inflammation and Tumorigenesis Associated with Gut Microbiota Alterations.
abstract: High mucosal and fecal concentrations of the antimicrobial siderophore-binding peptide Lipocalin-2 (Lcn2) are observed in inflammatory bowel disease. However, Lcn2 function in chronic intestinal inflammation remains unclear. Here, we demonstrate that Lcn2 protects from early-onset colitis and spontaneous emergence of right-sided colonic tumors resulting from IL-10 deficiency. Exacerbated inflammation in Lcn2(-/-)/Il10(-/-) mice is driven by IL-6, which also controls tumorigenesis. Lcn2(-/-)/Il10(-/-) mice exhibit profound alterations in gut microbial composition, which contributes to inflammation and tumorigenesis, as demonstrated by the transmissibility of the phenotype and protection conferred by antibiotics. Specifically, facultative pathogenic Alistipes spp. utilize enterobactin as iron source, bloom in Lcn2(-/-)/Il10(-/-) mice, and are sufficient to induce colitis and right-sided tumors when transferred into Il10(-/-) mice. Our results demonstrate that Lcn2 protects against intestinal inflammation and tumorigenesis associated with alterations in the microbiota.
authors.affiliation: Division of Internal Medicine I (Gastroenterology, Endocrinology and Metabolism), Department of Medicine, Medical University Innsbruck, Innsbruck 6020, Austria. Electronic address: alexander.moschen@i-med.ac.at.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Moschen
authors.affiliation: Division of Internal Medicine I (Gastroenterology, Endocrinology and Metabolism), Department of Medicine, Medical University Innsbruck, Innsbruck 6020, Austria.
authors.forename: Romana R
authors.initials: RR
authors.lastname: Gerner
authors.affiliation: Max Planck Institute for Evolutionary Biology, Plön 24308, Germany; Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Kiel 24118, Germany.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medical Genetics, Molecular and Clinical Pharmacology, Division of Translational Cell Genetics, Medical University Innsbruck, Innsbruck 6020, Austria.
authors.forename: Victoria
authors.initials: V
authors.lastname: Klepsch
authors.affiliation: Division of Internal Medicine I (Gastroenterology, Endocrinology and Metabolism), Department of Medicine, Medical University Innsbruck, Innsbruck 6020, Austria.
authors.forename: Timon E
authors.initials: TE
authors.lastname: Adolph
authors.affiliation: Division of Internal Medicine I (Gastroenterology, Endocrinology and Metabolism), Department of Medicine, Medical University Innsbruck, Innsbruck 6020, Austria.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Reider
authors.affiliation: Division of Bioinformatics, Biocenter Innsbruck, Medical University Innsbruck, Innsbruck 6020, Austria.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hackl
authors.affiliation: Division of Internal Medicine I (Gastroenterology, Endocrinology and Metabolism), Department of Medicine, Medical University Innsbruck, Innsbruck 6020, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pfister
authors.affiliation: Charité Hospital, CCM, Laboratory for Molecular Genetics, Polymicrobial Infections and Bacterial Biofilms and Department of Medicine, Gastroenterology, Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schilling
authors.affiliation: Department of Pathology, Medical University Innsbruck, Innsbruck 6020, Austria.
authors.forename: Patrizia L
authors.initials: PL
authors.lastname: Moser
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Kempster
authors.affiliation: Charité Hospital, CCM, Laboratory for Molecular Genetics, Polymicrobial Infections and Bacterial Biofilms and Department of Medicine, Gastroenterology, Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Swidsinski
authors.affiliation: Division of Hygiene and Medical Microbiology, Department of Hygiene, Microbiology and Social Medicine, Medical University Innsbruck, Innsbruck 6020, Austria.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Orth Höller
authors.affiliation: Division of Internal Medicine VI (Infectious Diseases, Immunology, Rheumatology and Pneumology), Department of Medicine, Medical University Innsbruck, Innsbruck 6020, Austria.
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
authors.affiliation: Max Planck Institute for Evolutionary Biology, Plön 24308, Germany; Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Kiel 24118, Germany.
authors.forename: John F
authors.initials: JF
authors.lastname: Baines
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Arthur
authors.initials: A
authors.lastname: Kaser
authors.affiliation: Division of Internal Medicine I (Gastroenterology, Endocrinology and Metabolism), Department of Medicine, Medical University Innsbruck, Innsbruck 6020, Austria. Electronic address: herbert.tilg@i-med.ac.at.
authors.forename: Herbert
authors.initials: H
authors.lastname: Tilg
mesh_terms: D000818:Animals; D001439:Bacteroides / Q000254:growth & development; D063646:Carcinogenesis; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D000069196:Gastrointestinal Microbiome; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007414:Intestinal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D000071068:Lipocalin-2 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D015850:Interleukin-6; D000071068:Lipocalin-2; D016753:Interleukin-10