2. Academic Validation
  3. Short-term post-fast refeeding enhances intestinal stemness via polyamines

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

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. alpaslan.tasdogan@uk-essen.de.
  • 17 Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, MIT, Cambridge, MA, USA. ohyilmaz@mit.edu.
  • 18 Broad Institute of Harvard and MIT, Cambridge, MA, USA. ohyilmaz@mit.edu.
  • 19 Department of Pathology, Beth Israel Deaconess Medical Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ohyilmaz@mit.edu.
  • # Contributed equally.
PMID: 39169180 DOI: 10.1038/s41586-024-07840-z
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.

Figures
Products