Gut epithelium modifies enteric behaviors during nutritional adversity via distinct peptidergic signaling axes

Interorgan signaling events are emerging as key regulators of behavioral plasticity. The foregut and hindgut circuits of the C. elegans enteric nervous system (ENS) control feeding and defecation behavior, respectively. Here we show that epithelial cells in the midgut integrate feeding state information to control these behavioral outputs via releasing distinct neuropeptidergic signals. In favorable conditions, insulin and non-insulin peptides released from midgut epithelia activate foregut and hindgut enteric neurons, respectively, to sustain normal feeding and defecation behavior. During food scarcity, altered insulin signaling from sensory neurons activates the transcription factor DAF-16/FoxO in midgut epithelia, which blocks both peptidergic signaling axes to the ENS via transcriptionally shutting down the intestinal neuropeptide secretion machinery. Our findings demonstrate that midgut epithelial cells act as integrators to relay internal state information to distinct parts of the enteric nervous system to control animal behavior. Overall design: RNA-seq profiling of dauer stage animals in which DAF-16/FoxO is specifically depleted from the intestinal epithelial cells using the AID2 system.

器官间信号事件正逐渐成为行为可塑性的关键调控因子。秀丽隐杆线虫（C. elegans）的肠神经系统（enteric nervous system, ENS）前肠与后肠环路分别调控进食与排遗行为。本研究证实，中肠上皮细胞可整合进食状态信息，通过释放不同的神经肽能信号调控上述行为输出。在适宜环境条件下，中肠上皮细胞释放的胰岛素肽与非胰岛素肽可分别激活前肠与后肠的肠神经元，以维持正常的进食与排遗行为。在食物匮乏时，感觉神经元传来的胰岛素信号发生改变，激活中肠上皮细胞中的转录因子DAF-16/FoxO；该因子可通过转录水平抑制肠道神经肽分泌系统，阻断两条通往肠神经系统的神经肽信号通路。本研究结果表明，中肠上皮细胞可作为整合枢纽，将机体内部状态信息传递至肠神经系统的不同区域，从而调控动物行为。实验整体设计：采用AID2系统，对肠道上皮细胞中特异性敲降DAF-16/FoxO的持久态（dauer stage）秀丽隐杆线虫进行RNA测序（RNA-seq）转录组分析。