Parallel enterocyte caspase and cytokine responses couple hypoxia to reoxygenation-dependent intestinal regeneration in Drosophila

Intestinal oxygen availability fluctuates during both normal physiology and disease, yet how the intestinal epithelium adapts to these changing environments remains poorly understood. Using the adult Drosophila intestine, we show that hypoxia and reoxygenation drive distinct phases of an epithelial damage and repair response. Hypoxia induces two parallel responses in largely separate enterocyte populations: an AMPK-p53-dependent response that primes enterocytes for apoptosis, and an independent Upd cytokine response that activates JAK-STAT signaling in intestinal stem cells (ISCs). Despite activation of both pathways during hypoxia, neither apoptosis nor ISC proliferation occurs until oxygen is restored. Upon reoxygenation, enterocyte loss and ISC proliferation proceed together and both are required for recovery of intestinal length. We further show that HIF-1/Sima is dispensable in enterocytes but required in progenitor cells for reoxygenation-induced proliferation. Finally, repeated episodes of hypoxia-reoxygenation shorten lifespan, and this is exacerbated by enterocyte p53 knockdown. Together, these findings indicate that the epithelium adapts to fluctuating oxygen by coordinating damage and repair responses in space and time.