Short-term post-fast refeeding enhances intestinal stemness via polyamines PMID: 39169180

ADC Targets in Oncology

2026-04-10

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

Nature. 2024 Sep;633(8031):895-904. doi: 10.1038/s41586-024-07840-z.

Shinya Imada ^# ¹ , Saleh Khawaled ^# ¹ , Heaji Shin ¹ , Sven W Meckelmann ² , Charles A Whittaker ³ , Renan Oliveira Corrêa ¹ ⁴ ⁵ , Chiara Alquati ¹ ⁶ , Yixin Lu ¹ , Guodong Tie ⁷ ⁸ , Dikshant Pradhan ³ , Gizem Calibasi-Kocal ¹ ⁹ , Luiza Martins Nascentes Melo ¹⁰ , Gabriele Allies ¹⁰ , Jonas Rösler ¹⁰ , Pia Wittenhofer ² , Jonathan Krystkiewicz ¹⁰ , Oliver J Schmitz ² , Jatin Roper ¹¹ ¹² , Marco Aurelio Ramirez Vinolo ⁴ ⁵ , Luigi Ricciardiello ⁶ ¹³ , Evan C Lien ¹⁴ , Matthew G Vander Heiden ¹ , Ramesh A Shivdasani ⁷ ⁸ , Chia-Wei Cheng ¹ ¹⁵ , Alpaslan Tasdogan ¹⁶ , Ömer H Yilmaz ¹⁷ ¹⁸ ¹⁹

Affiliations

1. Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, MIT, Cambridge, MA, USA.
2. Applied Analytical Chemistry, University of Duisburg-Essen, Essen, Germany.
3. Barbara K. Ostrom (1978) Bioinformatics and Computing Core Facility, Swanson Biotechnology Center, Koch Institute at the MIT, Cambridge, MA, USA.
4. Laboratory of Immunoinflammation, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, São Paulo, Brazil.
5. Obesity and Comorbidities Research Center (OCRC), University of Campinas, São Paulo, Brazil.
6. Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
7. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
8. Department of Medicine, Harvard Medical School, Boston, MA, USA.
9. Department of Translational Oncology, Institute of Oncology, Dokuz Eylul University, Izmir-Turkey, Turkey.
10. Department of Dermatology, University Hospital Essen and German Cancer Consortium, Essen, Germany.
11. Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC, USA.
12. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
13. Department of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center, Houston, TX, USA.
14. Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.
15. Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA.
16. Department of Dermatology, University Hospital Essen and German Cancer Consortium, Essen, Germany. [email protected].
17. Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, MIT, Cambridge, MA, USA. [email protected].
18. Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].
19. Department of Pathology, Beth Israel Deaconess Medical Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
# Contributed equally.

Abstract

For over a century, fasting regimens have improved health, lifespan and tissue regeneration in diverse organisms, including humans^1-6. 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.