Post-fast refeeding enhances intestinal stem cell-mediated regeneration and tumourigenesis through mTORC1-dependent polyamine synthesis

Abstract

For more than a century, fasting regimens have improved health, lifespan, and tissue regeneration in diverse organisms, including humans. However, how fasting and post-fast refeeding impact 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+ intestinal stem cells (ISCs), and loss of the tumour suppressor Apc in ISCs under post-fast refeeding leads to a higher tumour incidence in the small intestine and colon than in the fasted or ad libitum (AL) fed states. This demonstrates that post-fast refeeding is a distinct state. Mechanistically, we discovered that robust induction of mTORC1 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 tumourigenic effects of post-fast refeeding. Thus, fast-refeeding cycles must be carefully considered when planning diet-based strategies for regeneration without increasing cancer risk, as post-fast refeeding leads to a burst not only in stem cell-driven regeneration but also in tumourigenicity.

Nutrient metabolism in regulating intestinal stem cell homeostasis

“…Indeed, studies have demonstrated that both HFD feeding and fast-refeeding promote tumorigenesis in Apc mutant mice by enhancing ISC stemness. 60,66 Thus, it would be crucial to determine whether ISCs exhibit similar or distinct features during normal intestinal regeneration and the early stages of tumorigenesis. Moreover, investigating whether long-term calorie restriction or ketogenic diet may promote tumorigenicity in the intestine is imperative.…”

“…Refeeding for 24 À 72 h after 24 h-fasting shows augmentation in both ISC and progenitor cell proliferation. 60 Further investigations showed that fast-refeeding activates protein synthesis via a mammalian target of rapamycin complex 1 (mTORC1)-stimulated polyamine metabolism programme. Protein synthesis also increases the risk of tumorigenesis.…”

“…Indeed, post-fast refeeding in Apc-null mice enhances polyp formation in both small and large intestines. 60 On the other hand, prolonged calorie restriction (CR) not only augments ISC function but also increases OLFM4 + stem cells and Paneth cell numbers. 57,61 CR exerts its effects mainly through mTORC1 (Figure 2A).…”