Background and Aims

Dietary fat intake is associated with increased risk of colorectal cancer (CRC). We examined the role of high-fat diet (HFD) in driving CRC through modulating gut microbiota and metabolites.

Methods

HFD or control diet was fed to mice littermates in CRC mouse models of an azoxymethane (AOM) model and Apc^min/+ model, with or without antibiotics cocktail treatment. Germ-free mice for fecal microbiota transplantation were used for validation. Gut microbiota and metabolites were detected using metagenomic sequencing and high-performance liquid chromatography–mass spectrometry, respectively. Gut barrier function was determined using lipopolysaccharides level and transmission electron microscopy.

Results

HFD promoted colorectal tumorigenesis in both AOM-treated mice and Apc^min/+ mice compared with control diet–fed mice. Gut microbiota depletion using antibiotics attenuated colon tumor formation in HFD-fed mice. A significant shift of gut microbiota composition with increased pathogenic bacteria Alistipes sp. Marseille-P5997 and Alistipes sp. 5CPEGH6, and depleted probiotic Parabacteroides distasonis, along with impaired gut barrier function was exhibited in HFD-fed mice. Moreover, HFD-modulated gut microbiota promotes colorectal tumorigenesis in AOM-treated germ-free mice, indicating gut microbiota was essential in HFD-associated colorectal tumorigenesis. Gut metabolites alteration, including elevated lysophosphatidic acid, which was confirmed to promote CRC cell proliferation and impair cell junction, was also observed in HFD-fed mice. Moreover, transfer of stools from HFD-fed mice to germ-free mice without interference increased colonic cell proliferation, impaired gut barrier function, and induced oncogenic genes expression.

Conclusions

HFD drives colorectal tumorigenesis through inducing gut microbial dysbiosis, metabolomic dysregulation with elevated lysophosphatidic acid, and gut barrier dysfunction in mice.

中文翻译：

---

高脂肪饮食通过调节肠道微生物群和代谢物促进结直肠肿瘤的发生

 背景和目标

膳食脂肪摄入量与结直肠癌 (CRC) 风险增加相关。我们研究了高脂饮食 (HFD) 通过调节肠道微生物群和代谢物来驱动 CRC 的作用。

 方法

在氧化偶氮甲烷 (AOM) 模型和Apc ^min/+模型的 CRC 小鼠模型中，用 HFD 或对照饮食喂养小鼠同窝小鼠，使用或不使用抗生素鸡尾酒治疗。使用用于粪便微生物移植的无菌小鼠进行验证。分别使用宏基因组测序和高效液相色谱-质谱法检测肠道微生物群和代谢物。使用脂多糖水平和透射电子显微镜测定肠道屏障功能。

 结果

与对照饮食喂养的小鼠相比，HFD 促进了 AOM 处理的小鼠和Apc ^min/+小鼠的结直肠肿瘤发生。使用抗生素消除肠道微生物群可减少高脂饮食小鼠结肠肿瘤的形成。随着致病菌Alistipes sp 的增加，肠道微生物群组成发生显着变化。马赛-P5997和Alitipes sp。 HFD 喂养的小鼠中表现出5CPEGH6和益生菌Parabacteroides distasonis耗尽以及肠道屏障功能受损。此外，HFD 调节的肠道微生物群促进 AOM 处理的无菌小鼠的结直肠肿瘤发生，表明肠道微生物群在 HFD 相关结直肠肿瘤发生中至关重要。在 HFD 喂养的小鼠中也观察到肠道代谢物的改变，包括溶血磷脂酸升高，这被证实会促进 CRC 细胞增殖并损害细胞连接。此外，在没有干扰的情况下将高脂饮食小鼠的粪便转移到无菌小鼠体内会增加结肠细胞增殖，损害肠道屏障功能，并诱导致癌基因表达。

 结论

HFD 通过诱导肠道微生物失调、溶血磷脂酸升高引起的代谢组失调以及小鼠肠道屏障功能障碍来驱动结直肠肿瘤的发生。