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

Nature. 2024 Sep;633(8031):895-904. doi: 10.1038/s41586-024-07840-z. Epub 2024 Aug 21.

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.

MeSH terms

  • Adenomatous Polyposis Coli Protein / deficiency
  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli Protein / metabolism
  • Animals
  • Carcinogenesis* / metabolism
  • Carcinogenesis* / pathology
  • Cell Proliferation
  • Colon* / cytology
  • Colon* / metabolism
  • Colon* / pathology
  • Diet
  • Fasting* / physiology
  • Feeding Behavior* / physiology
  • Female
  • Intestine, Small* / cytology
  • Intestine, Small* / metabolism
  • Intestine, Small* / pathology
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Polyamines* / metabolism
  • Protein Biosynthesis
  • Receptors, G-Protein-Coupled / metabolism
  • Regeneration / physiology
  • Risk Assessment
  • Stem Cells* / cytology
  • Stem Cells* / metabolism
  • Stem Cells* / pathology
  • Time Factors

Substances

  • adenomatous polyposis coli protein, mouse
  • Lgr5 protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Polyamines
  • Receptors, G-Protein-Coupled
  • Adenomatous Polyposis Coli Protein