Cholinergic neurons trigger epithelial Ca 2+ currents to heal the gut.

A fundamental and unresolved question in regenerative biology is how tissues return to homeostasis after injury. Answering this question is essential for understanding the etiology of chronic disorders such as inflammatory bowel diseases and cancer 1 . We used the Drosophila midgut 2 to investigate this and discovered that during regeneration a subpopulation of cholinergic 3 neurons triggers Ca 2+ currents among intestinal epithelial cells, the enterocytes, to promote return to homeostasis. We found that down-regulation of the conserved cholinergic enzyme Acetylcholinesterase 4 in the gut epithelium enables acetylcholine from specific TNF/Egr 5 -sensing cholinergic neurons to activate nicotinic receptors in innervated enterocytes. This activation triggers high Ca 2+ that spreads in the epithelium through Inx2/Inx7 gap junctions 6 , promoting enterocyte maturation followed by reduction of proliferation and inflammation. Disrupting this process causes chronic injury consisting of ion imbalance, Yki/Yap activation 7 , cell death and increase of inflammatory cytokines reminiscent of inflammatory bowel diseases 8 . Altogether, the conserved cholinergic pathway facilitates epithelial Ca 2+ currents that heal the intestinal epithelium. Our findings demonstrate nerve- and bioelectric 9 -dependent intestinal regeneration and advance our current understanding of how a tissue returns to homeostasis after injury.