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

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Imada, Shinya ; Khawaled, Saleh ; Shin, Heaji ; Meckelmann, Sven W. ; Whittaker, Charles A. ; Correa, Renan Oliveira ; Alquati, Chiara ; Lu, Yixin ; Tie, Guodong ; Pradhan, Dikshant ; Calibasi-Kocal, Gizem ; Melo, Luiza Martins Nascentes ; Allies, Gabriele ; Roesler, 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 ; Yilmaz, Omer H.

• Document type: Journal article
• Source: Nature; v. N/A, p. 28-pg., 2024-08-21.

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. (AU)

• FAPESP's process: 19/02640-3 - Role of the high-fiber diet on the function of the intestinal stem cells and their niche
• Grantee: Renan Oliveira Corrêa
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 18/15313-8 - Investigation of the molecular mechanisms involved in the interaction between microbiota-derived metabolites and host cells during inflammation
• Grantee: Marco Aurélio Ramirez Vinolo
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 16/23142-3 - Interaction between HIF-1 and short-chain fatty acids in the intestine: what is the role of HIF-1 acetylation?
• Grantee: Renan Oliveira Corrêa
• Support Opportunities: Scholarships in Brazil - Doctorate