Cholinergic neurons trigger epithelial Ca²⁺ 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 aetiology of chronic disorders such as inflammatory bowel diseases and cancer¹. We used the Drosophila midgut² to investigate this and discovered that during regeneration a subpopulation of cholinergic³ neurons triggers Ca²⁺ currents among intestinal epithelial cells, the enterocytes, to promote return to homeostasis. We found that downregulation of the conserved cholinergic enzyme acetylcholinesterase⁴ in the gut epithelium enables acetylcholine from specific Egr⁵ (TNF in mammals)-sensing cholinergic neurons to activate nicotinic receptors in innervated enterocytes. This activation triggers high Ca²⁺, which spreads in the epithelium through Innexin2-Innexin7 gap junctions⁶, promoting enterocyte maturation followed by reduction of proliferation and inflammation. Disrupting this process causes chronic injury consisting of ion imbalance, Yki (YAP in humans) activation⁷, cell death and increase of inflammatory cytokines reminiscent of inflammatory bowel diseases⁸. Altogether, the conserved cholinergic pathway facilitates epithelial Ca²⁺ currents that heal the intestinal epithelium. Our findings demonstrate nerve- and bioelectric⁹-dependent intestinal regeneration and advance our current understanding of how a tissue returns to homeostasis after injury.