麻省理工学院Ömer H. Yilmaz小组的最新研究揭示了生酮饮食通过脂类而非酮类介导肠道肿瘤发生。相关论文发表在2026年7月15日出版的《自然》杂志上。

在本研究中，该课题组结合饮食、遗传和代谢操作在自发性肠腺瘤形成的小鼠模型中，剖析了系统性和上皮性酮生在肠癌中的作用。该团队发现KD加速了它们的负担，缩短了生存期，不依赖于酮代谢产物。通过对生酮途径的遗传操纵，研究团队调节了局部和全身酮代谢物的产生；然而，生酮酶3-羟基-3-甲基戊二酰辅酶A合成酶2的抑制和增强以及酮解的破坏都不能改变肿瘤的发生。

肠道中PPARα/δ/γ的联合缺失会减弱KD驱动的肠道干细胞的扩增、增殖和克隆原性，而通过CPT1A缺失抑制下游脂肪酸氧化则会限制KD下腺瘤的形成，从而将肿瘤的发生与膳食脂质的脂肪酸氧化联系起来，而不是脂质积累。这些发现表明，饮食中的脂质含量，通过脂肪酸氧化而不是酮代谢，影响肠道肿瘤的发生，并强调需要细致地考虑在遗传易感人群中预防癌症的饮食策略。

据悉，饮食组成通过调节营养可利用性、代谢状态和细胞动力学来塑造组织功能和疾病风险。在胃肠道中，致肥性高脂肪饮食可增强小肠干细胞活性和肿瘤发生。然而，生酮饮食（KDs）的影响仍然知之甚少，它含有更高的脂质含量，但会减少循环胰岛素并诱导生酮。这对于家族性腺瘤性息肉患者尤其重要，因为他们面临着患小肠肿瘤的高风险。

附：英文原文

Title: Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones

Author: Shay, Jessica E. S., Chi, Fangtao, Tzouanas, Constantine N., Han, Shixun, Zhang, Xiao, Ten Hoeve, Johanna, Williams, Kevin J., Neptun, Seda, Sever, Tolga, Fuentes, Isabela, Bhatia, Sangeeta N., Calibasi-Kocal, Gizem, Vander Heiden, Matthew G., Shalek, Alex K., Yilmaz, mer H.

Issue&Volume: 2026-07-15

Abstract: Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state and cellular dynamics1. In the gastrointestinal tract, obesogenic high-fat diets enhance small-intestinal stem cell activity and tumorigenesis2. However, the impact of ketogenic diets (KDs), which contain even higher lipid content but reduce circulating insulin and induce ketogenesis, remains poorly understood3. This is particularly relevant for patients with familial adenomatous polyposis who face a high risk of small-intestinal tumours4. Here we combine dietary, genetic and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone metabolites. Through genetic manipulation of the ketogenic pathway, we modulate the production of local and systemic ketone metabolites; however, neither inhibition nor augmentation of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 nor disruption of ketolysis altered tumorigenesis. Combined intestinal loss of PPARα/δ/γ attenuates KD-driven intestinal stem cell expansion, proliferation and clonogenicity, whereas inhibition of downstream fatty acid oxidation through CPT1A loss limits adenoma formation specifically under KD, linking tumour initiation to fatty acid oxidation of dietary lipids rather than lipid accumulation. These findings reveal that dietary lipid content, through fatty acid oxidation rather than ketone metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.

DOI: 10.1038/s41586-026-10779-y

Source: https://www.nature.com/articles/s41586-026-10779-y