title: High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity.
abstract: Several features common to a Western lifestyle, including obesity and low levels of physical activity, are known risk factors for gastrointestinal cancers. There is substantial evidence suggesting that diet markedly affects the composition of the intestinal microbiota. Moreover, there is now unequivocal evidence linking dysbiosis to cancer development. However, the mechanisms by which high-fat diet (HFD)-mediated changes in the microbial community affect the severity of tumorigenesis in the gut remain to be determined. Here we demonstrate that an HFD promotes tumour progression in the small intestine of genetically susceptible, K-ras(G12Dint), mice independently of obesity. HFD consumption, in conjunction with K-ras mutation, mediated a shift in the composition of the gut microbiota, and this shift was associated with a decrease in Paneth-cell-mediated antimicrobial host defence that compromised dendritic cell recruitment and MHC class II molecule presentation in the gut-associated lymphoid tissues. When butyrate was administered to HFD-fed K-ras(G12Dint) mice, dendritic cell recruitment in the gut-associated lymphoid tissues was normalized, and tumour progression was attenuated. Importantly, deficiency in MYD88, a signalling adaptor for pattern recognition receptors and Toll-like receptors, blocked tumour progression. The transfer of faecal samples from HFD-fed mice with intestinal tumours to healthy adult K-ras(G12Dint) mice was sufficient to transmit disease in the absence of an HFD. Furthermore, treatment with antibiotics completely blocked HFD-induced tumour progression, suggesting that distinct shifts in the microbiota have a pivotal role in aggravating disease. Collectively, these data underscore the importance of the reciprocal interaction between host and environmental factors in selecting a microbiota that favours carcinogenesis, and they suggest that tumorigenesis is transmissible among genetically predisposed individuals.
authors.affiliation: 1] Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany [2].
authors.forename: Manon D
authors.initials: MD
authors.lastname: Schulz
authors.affiliation: 1] Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany [2].
authors.forename: Ciğdem
authors.initials: C
authors.lastname: Atay
authors.affiliation: 1] Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany [2].
authors.forename: Jessica
authors.initials: J
authors.lastname: Heringer
authors.affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany.
authors.forename: Franziska K
authors.initials: FK
authors.lastname: Romrig
authors.affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Schwitalla
authors.affiliation: Department of Molecular Biology and Genetics, Bogazici University, 34342 Bebek, Istanbul, Turkey.
authors.forename: Begüm
authors.initials: B
authors.lastname: Aydin
authors.affiliation: 1] Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany [2] German Cancer Consortium (DKTK), 69120 Heidelberg, Germany [3] German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Ziegler
authors.affiliation: 1] Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany [2] German Cancer Consortium (DKTK), 69120 Heidelberg, Germany [3] German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Varga
authors.affiliation: Department of Internal Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Reindl
authors.affiliation: Microarray and Deep-Sequencing Core Facility, University Medical Center Göttingen, 37077 Göttingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pommerenke
authors.affiliation: Microarray and Deep-Sequencing Core Facility, University Medical Center Göttingen, 37077 Göttingen, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Salinas-Riester
authors.affiliation: Institute for Mathematical Statistics, Technical University Munich, 81675 Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Böck
authors.affiliation: 1] Department of Gastrointestinal Microbiology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany [2].
authors.forename: Carl
authors.initials: C
authors.lastname: Alpert
authors.affiliation: Department of Gastrointestinal Microbiology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Blaut
authors.affiliation: Center for Bioinformatics and Computational Biology, Delaware Biotechnology Institute, University of Delaware, Newark, Delaware 19711, USA.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Polson
authors.affiliation: Institute of Pathology, Ludwig Maximilians University, 80337 Munich, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Brandl
authors.affiliation: 1] German Cancer Consortium (DKTK), 69120 Heidelberg, Germany [2] German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [3] Institute of Pathology, Ludwig Maximilians University, 80337 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.affiliation: 1] Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany [2] German Cancer Consortium (DKTK), 69120 Heidelberg, Germany [3] German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Florian R
authors.initials: FR
authors.lastname: Greten
authors.affiliation: Center for Bioinformatics and Computational Biology, Delaware Biotechnology Institute, University of Delaware, Newark, Delaware 19711, USA.
authors.forename: Shawn W
authors.initials: SW
authors.lastname: Polson
authors.affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany.
authors.forename: Melek C
authors.initials: MC
authors.lastname: Arkan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D063646:Carcinogenesis / Q000187:drug effects*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004041:Dietary Fats / Q000009:adverse effects*; D018450:Disease Progression; D064806:Dysbiosis / Q000139:chemically induced* / Q000382:microbiology*; D007413:Intestinal Mucosa / Q000276:immunology; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000382:microbiology*; D007422:Intestines / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D009765:Obesity / Q000139:chemically induced / Q000382:microbiology; D056692:Prebiotics
chemical_list: D000900:Anti-Bacterial Agents; D002087:Butyrates; D004041:Dietary Fats; D056692:Prebiotics