Short-term post-fast refeeding enhances intestinal stemness via polyamines

• 成果类型: Article
• 署名作者: Imada, Shinya; Khawaled, Saleh; Shin, Heaji; Meckelmann, Sven W.; Whittaker, Charles A.; Correa, Renan Oliveira; Alquati, Chiara; Lu, Yixin; Tie, Guodong; Pradhan, Dikshant; Calibasi-Kocal, Gizem; Melo, Luiza Martins Nascentes; Allies, Gabriele; Roesler, Jonas; Wittenhofer, Pia; Krystkiewicz, Jonathan; Schmitz, Oliver J.; Roper, Jatin; Vinolo, Marco Aurelio Ramirez; Ricciardiello, Luigi; Lien, Evan C.; Vander Heiden, Matthew G.; Shivdasani, Ramesh A.; Cheng, Chia-Wei; Tasdogan, Alpaslan; Yilmaz, Oemer H.
• 署名单位: Massachusetts Institute of Technology (MIT); University of Duisburg Essen; Massachusetts Institute of Technology (MIT); Universidade de Sao Paulo; Universidade Estadual de Campinas; Universidade Estadual de Campinas; University of Bologna; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Dokuz Eylul University; University of Duisburg Essen; Helmholtz Association; German Cancer Research Center (DKFZ); Duke University; Duke University; University of Texas System; UTMD Anderson Cancer Center; Van Andel Institute; Columbia University; NewYork-Presbyterian Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Massachusetts General Hospital; Harvard University; Harvard Medical School
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6586
• DOI: 10.1038/s41586-024-07840-z
• 发表日期: 2024-09-26
• 关键词: molecular-mechanisms; calorie restriction; cell homeostasis; in-vitro; diet; inhibitor; metabolism; cancer; identification; regeneration

摘要

For over a century, fasting regimens have improved health, lifespan and tissue regeneration in diverse organisms, including humans1-6. 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. Post-fast refeeding increases intestinal stem cell function and tumour formation by augmenting protein synthesis via polyamine metabolism.