Neuronal programming by microbiota regulates intestinal physiology
Neuronal programming by microbiota regulates intestinal physiology
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微生物群的神经元编程调节肠道生理学
DOI：
10.1038/s41586-020-1975-8
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发表时间：
2020-02-05
期刊：
影响因子：
64.8
通讯作者：
Pachnis, Vassilis
中科院分区：
文献类型：
--
作者：
Obata, Yuuki;Castano, Alvaro;Pachnis, Vassilis
内脏器官功能的神经控制对于体内平衡和健康是必不可少的。肠道蠕动对消化生理和宿主防御至关重要，在胃肠道疾病中常常失调[1]。发光因素，如饮食和微生物区系，调节肠道运动的神经发生程序(2-5)，但潜在的分子机制仍不清楚。在这里，我们展示了转录因子芳香烃受体(AHR)在肠道神经回路中作为生物传感器的功能，将它们的功能输出与肠腔的微生物环境联系起来。利用代表不同肠段和微生物区系状态的小鼠肠道神经元的核RNA测序，我们证明了结肠的内在神经网络显示出独特的转录图谱，该转录图谱受宿主遗传程序和微生物定植的共同影响。微生物区系诱导的AHR在远端胃肠道神经元中的表达使这些神经元能够对管腔环境做出反应，并诱导神经元特异性效应机制的表达。神经元特异性的AhR缺失，或其负反馈调节因子CyP1A1的结构性过表达，会导致结肠蠕动活性降低，与在微生物区系耗尽的小鼠中观察到的情况类似。最后，在抗生素治疗的小鼠的肠神经细胞中表达AhR可以部分恢复肠道运动。总之，我们的实验将肠道神经元中的AHR信号识别为一个调节节点，它将肠腔环境与肠道神经回路的生理输出整合在一起，以维持肠道的稳态和健康。在小鼠模型中，肠道神经元中的芳香烃受体信号被揭示为一种机制，通过将肠腔环境与肠道神经回路的生理结合起来，帮助维持肠道的稳态。
Neural control of the function of visceral organs is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence, and is often dysregulated in gastrointestinal disorders(1). Luminal factors, such as diet and microbiota, regulate neurogenic programs of gut motility(2-5), but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor aryl hydrocarbon receptor (AHR) functions as a biosensor in intestinal neural circuits, linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons that represent distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles that are controlled by the combined effects of host genetic programs and microbial colonization. Microbiota-induced expression of AHR in neurons of the distal gastrointestinal tract enables these neurons to respond to the luminal environment and to induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr, or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in the enteric neurons of mice treated with antibiotics partially restores intestinal motility. Together, our experiments identify AHR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits to maintain gut homeostasis and health.In a mouse model, aryl hydrocarbon receptor signalling in enteric neurons is revealed as a mechanism that helps to maintain gut homeostasis by integrating the luminal environment with the physiology of intestinal neural circuits.