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首页> 外文期刊>Nature >High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity
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High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity

机译：高脂饮食介导的营养不良与肥胖无关地促进肠道致癌作用

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摘要

西餐,尤其是高脂肪西餐已被发现与胃肠癌有关。现在,Manon Schulz等人通过一个小鼠模型发现,高脂肪食物能通过改变肠道微生物群的组成和改变免疫环境来以独立于肥胖的方式促进肠道肿瘤发生。虽然抗生素能阻止饮食脂肪对肿瘤的促进作用,但将来自吃高脂肪食物的小鼠的粪便转移给在遗传上易患肠癌、但喂饲正常食物的小鼠便足以促进肿瘤发生。这些发现显示了饮食、微生物群、免疫反应和癌症之间的复杂相互作用,也许能为防癌提供新途径。%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 firom 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.
机译：西餐,尤其是高脂肪西餐已被发现与胃肠癌有关。现在,Manon Schulz等人通过一个小鼠模型发现,高脂肪食物能通过改变肠道微生物群的组成和改变免疫环境来以独立于肥胖的方式促进肠道肿瘤发生。虽然抗生素能阻止饮食脂肪对肿瘤的促进作用,但将来自吃高脂肪食物的小鼠的粪便转移给在遗传上易患肠癌、但喂饲正常食物的小鼠便足以促进肿瘤发生。这些发现显示了饮食、微生物群、免疫反应和癌症之间的复杂相互作用,也许能为防癌提供新途径。%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 firom 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.

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  • 来源
    《Nature》 |2014年第7523期|508-512B2|共6页
  • 作者

    Manon D.Schulz; Cigdem Atay; Jessica Heringer; Franziska K. Romrig; Sarah Schwitalla; Beguem Aydin; Paul K. Ziegler; Julia Varga; Wolfgang Reindl; Claudia Pommerenke; Gabriela Salinas-Riester; Andreas Boeck; Carl Alpert; Michael Blaut; Sara C. Poison; Lydia Brandl; Thomas Kirchner; Florian R. Greten; Shawn W. Poison; Melek C.Arkan;

  • 作者单位

    Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany;

    Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany;

    Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany;

    Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany;

    Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany;

    Department of Molecular Biology and Genetics, Bogazici University, 34342 Bebek, Istanbul, Turkey;

    Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany,German Cancer Consortium (DKTK), 69120 Heidelberg, Germany,German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;

    Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany,German Cancer Consortium (DKTK), 69120 Heidelberg, Germany,German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;

    Department of Internal Medicine Ⅱ, Universitatsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany;

    Microarray and Deep-Sequencing Core Facility, University Medical Center Gottingen, 37077 Goettingen, Germany;

    Microarray and Deep-Sequencing Core Facility, University Medical Center Gottingen, 37077 Goettingen, Germany;

    Institute for Mathematical Statistics, Technical University Munich, 81675 Munich, Germany;

    Department of Gastrointestinal Microbiology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany;

    Department of Gastrointestinal Microbiology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany;

    Center for Bioinformatics and Computational Biology, Delaware Biotechnology Institute, University of Delaware, Newark,Delaware 19711, USA;

    Institute of Pathology,Ludwig Maximilians University,80337 Munich, Germany;

    German Cancer Consortium (DKTK), 69120 Heidelberg, Germany,German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany,Institute of Pathology,Ludwig Maximilians University,80337 Munich, Germany;

    Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany,German Cancer Consortium (DKTK), 69120 Heidelberg, Germany,German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;

    Center for Bioinformatics and Computational Biology, Delaware Biotechnology Institute, University of Delaware, Newark,Delaware 19711, USA;

    Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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