1. Short-term post-fast refeeding enhances intestinal stemness via polyamines
- Author
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Imada, Shinya, Khawaled, Saleh, Shin, Heaji, Meckelmann, Sven W., Whittaker, Charles A., Corrêa, Renan Oliveira, Alquati, Chiara, Lu, Yixin, Tie, Guodong, Pradhan, Dikshant, Calibasi-Kocal, Gizem, Nascentes Melo, Luiza Martins, Allies, Gabriele, Rösler, 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, and Yilmaz, Ömer H.
- Abstract
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 Apcin 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.
- Published
- 2024
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