For over a century, fasting regimens have improved health, lifespan and tissue regeneration in diverse organisms, including humans^1,2,3,4,5,6. However, how fasting and post-fast refeeding affect adult stem cells and tumour formation has yet to be explored in depth. Here we demonstrate that post-fast refeeding increases intestinal stem cell (ISC) proliferation and tumour formation; post-fast refeeding augments the regenerative capacity of Lgr5⁺ ISCs, and loss of the tumour suppressor gene Apc in post-fast-refed ISCs leads to a higher tumour incidence in the small intestine and colon than in the fasted or ad libitum-fed states, demonstrating that post-fast refeeding is a distinct state. Mechanistically, we discovered that robust mTORC1 induction in post-fast-refed ISCs increases protein synthesis via polyamine metabolism to drive these changes, as inhibition of mTORC1, polyamine metabolite production or protein synthesis abrogates the regenerative or tumorigenic effects of post-fast refeeding. Given our findings, fast–refeeding cycles must be carefully considered and tested when planning diet-based strategies for regeneration without increasing cancer risk, as post-fast refeeding leads to a burst in stem-cell-driven regeneration and tumorigenicity.

一个多世纪以来，禁食方案改善了包括人类在内的各种生物体的健康、寿命和组织再生^1,2,3,4,5,6。然而，禁食和禁食后再喂养如何影响成体干细胞和肿瘤形成还有待深入探讨。在这里，我们证明禁食后再喂养会增加肠道干细胞 （ISC） 增殖和肿瘤形成;禁食后再喂养增强了 Lgr5⁺ ISCs 的再生能力，禁食后 ISC 中肿瘤抑制基因 Apc 的丢失导致小肠和结肠中的肿瘤发病率高于禁食或随意进食状态，表明禁食后再喂养是一种独特的状态。从机制上讲，我们发现禁食后 ISC 中强大的 mTORC1 诱导通过多胺代谢增加蛋白质合成以驱动这些变化，因为抑制 mTORC1、多胺代谢物产生或蛋白质合成消除了禁食后再喂养的再生或致瘤作用。鉴于我们的研究结果，在规划基于饮食的再生策略而不增加癌症风险时，必须仔细考虑和测试快速再喂养周期，因为快速再喂养后会导致干细胞驱动的再生和致瘤性爆发。