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

Shinya Imada, Saleh Khawaled, Heaji Shin, Sven W. Meckelmann, Charles A. Whittaker, Renan Oliveira Corrêa, Chiara Alquati, Yixin Lu, Guodong Tie, Dikshant Pradhan, Gizem Calibasi-Kocal, Luiza Martins Nascentes Melo, Gabriele Allies, Jonas Rösler, Pia Wittenhofer, Jonathan Krystkiewicz, Oliver J. Schmitz, Jatin Roper, Marco Aurelio Ramirez Vinolo, Luigi Ricciardiello, Evan C. Lien, Matthew G. Vander Heiden, Ramesh A. Shivdasani, Chia-Wei Cheng, Alpaslan Tasdogan () and Ömer H. Yilmaz ()
Additional contact information
Shinya Imada: MIT
Saleh Khawaled: MIT
Heaji Shin: MIT
Sven W. Meckelmann: University of Duisburg-Essen
Charles A. Whittaker: Koch Institute at the MIT
Renan Oliveira Corrêa: MIT
Chiara Alquati: MIT
Yixin Lu: MIT
Guodong Tie: Dana-Farber Cancer Institute
Dikshant Pradhan: Koch Institute at the MIT
Gizem Calibasi-Kocal: MIT
Luiza Martins Nascentes Melo: University Hospital Essen and German Cancer Consortium
Gabriele Allies: University Hospital Essen and German Cancer Consortium
Jonas Rösler: University Hospital Essen and German Cancer Consortium
Pia Wittenhofer: University of Duisburg-Essen
Jonathan Krystkiewicz: University Hospital Essen and German Cancer Consortium
Oliver J. Schmitz: University of Duisburg-Essen
Jatin Roper: Duke University
Marco Aurelio Ramirez Vinolo: University of Campinas
Luigi Ricciardiello: University of Bologna
Evan C. Lien: Van Andel Institute
Matthew G. Vander Heiden: MIT
Ramesh A. Shivdasani: Dana-Farber Cancer Institute
Chia-Wei Cheng: MIT
Alpaslan Tasdogan: University Hospital Essen and German Cancer Consortium
Ömer H. Yilmaz: MIT

Nature, 2024, vol. 633, issue 8031, 895-904

Abstract: 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 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.

Date: 2024
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DOI: 10.1038/s41586-024-07840-z

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