西方生活方式包括肥胖和低运动量等是胃肠道肿瘤的风险因子。有确凿的证据表明食物可以显著影响肠道微生物菌群。但是菌群失调和肿瘤发生之间的关系却相对含糊不清，高脂饮食介导的菌群改变是否影响肿瘤恶性程度也在未知之列。在该文中我们证明：对于肠易感肿瘤基因型K-rasG12Dint小鼠，高脂饮食促进肿瘤的发生，而且肿瘤发生与肥胖无关。高脂饮食与K-ras突变相结合，介导肠道菌群组成的转变，这种改变与潘氏细胞（帕内特细胞，Paneth cell）介导的宿主抗微生物反应下降有关，并损害了肠道相关淋巴组织中树突细胞（dendritic cell）的募集和主要组织相容性复合体II的分子呈递能力。用丁酸盐处理高脂饮食K-rasG12Dint小鼠，则树突细胞在肠道相关淋巴组织中的募集恢复正常，肿瘤的进展消弱。重要的是，模式识别受体和Toll样受体的信号衔接蛋白MYD88的缺陷可阻止肿瘤进展。将患肠道肿瘤的高脂饮食小鼠的排泄物转入健康成年K-rasG12Dint小鼠体内，小鼠可在无高脂饮食情况下诱发消化道肿瘤。此外，使用抗生素可以完全阻止高脂饮食诱导的肿瘤发生，表明肠道微生物的显著改变在恶性肿瘤发生中发挥着关键作用。以上数据表明宿主与环境因子之间的相关作用在肠道菌群选择中发挥了重要作用，肠道菌群影响肿瘤的发生；表明在有遗传倾向性的个体中，肿瘤的发生具有可传递性。

链接：http://www.nature.com/nature/journal/v514/n7523/full/nature13398.html

文题：High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity

摘要：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-rasG12Dint, 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-rasG12Dint 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-rasG12Dint 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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