GSE192482
Post-fast refeeding enhances intestinal stem cell mediated regeneration and tumorigenesis through mTORC1 signaling and polyamine
For more than a century, fasting regimens have been shown to improve health, lifespan, and tissue regeneration in diverse model organisms and humans. However, important questions remain regarding how fasting and refeeding cycles stimulate stem cell output and how this influences their role in early tumor formation. Here, we demonstrate that in the mammalian intestine, a short 24-hour fast followed by a 24-hour refeeding period (that is, post-fast refeeding) and not fasting itself elevates the stemness program and regenerative capacity of Lgr5+ intestinal stem cells (ISCs).  Furthermore, loss of the tumor suppressor APC in post-fast refed ISCs significantly boosts tumor incidence in the small intestine and colon compared to those in the fasted or ad libitum fed states. Mechanistically, robust induction of insulin-PI3K-mTORC1 signaling as well as elevated intestinal polyamines level increase protein synthesis in post-fast refed ISCs to mediate these changes as inhibition of mTORC1, polyamine, or protein synthesis abrogate the regenerative or tumorigenic effects of post-fast refeeding. Thus, our data indicate that post-fast refeeding leads to a burst not only in stem cell-driven regeneration but also in tumorigenicity and that careful consideration be given to fast-refeeding cycles when planning diet-based strategies. Overall design: One replicate each of intestinal stem  and progenitor cells isolated from mice feeding at will (al), fasted for 24 hours (f), fasted followed by refeeding at will for 24 hours (rf) and refeeding plus Rapamycin.