杜克大学一种新的肠内分泌细胞类型介导肠道和大脑如何交换来自营养素的信号

A new enteroendocrine cell type mediates how gut and brain exchange signals from nutrients

 

人们早就知道,肠道通过不同的途径与大脑相通,这些途径包括神经元激活,激素和免疫信号的释放。沿吸收性肠细胞之间的胃肠道散布的肠内分泌细胞(EEC)参与感知管腔营养物和细菌,并通过释放肠激素(例如缩胆囊素)间接地将其传递给大脑。然而,介导肠道信号转导到大脑的潜在机制仍然未被识别。

由杜克大学(美国北卡罗来纳州)医学和神经生物学系的DiegoV.Bohórquez博士领导的一项新研究表明,肠道内一种称为神经细胞的肠内分泌细胞与感觉神经纤维相通通过直接的细胞 - 神经接触。

为了追踪体内EEC和神经之间的电路,研究人员使用了一种改良的荧光狂犬病毒,它可以选择性地感染EEC并通过突触传播到神经上。通过灌肠给予小鼠的病毒不仅传播到结肠中的感觉神经元,而且传播到投射到脑干孤束核中的迷走神经元。这些发现表明存在神经上皮回路,其将肠腔与脑干连接,仅有一个突触。

 

另一方面,通过将单个EEC与感觉神经元共培养在体外重构神经上皮回路,以测试糖是否被迷走神经直接或通过EEC感知。单独培养的迷走神经元对葡萄糖刺激没有反应。相反,当感觉神经元与EEC共培养时,两种细胞类型之间形成可见的连接,葡萄糖刺激神经元中的动作电位。

 

使用光遗传学 - 一种利用闪光监测基因工程动物中特定个体​​细胞活动的技术 - 研究人员在体外和体内发现,在光刺激的情况下,葡萄糖引发的兴奋性突触后电流快达60ms在光敏EEC中。然而,在光刺激存在下,光抑制通道消除了迷走神经元中的葡萄糖刺激活性。这些数据表明,EEC需要将葡萄糖刺激从肠道快速转换为感觉神经元。

 

先前的数据确实支持这种能够快速将感觉信号从肠道传导到大脑的肠 - 脑神经连接的存在。其他研究人员表明,在营养物质到达肠道的几秒钟内,参与中枢控制饲料和能量消耗的下丘脑神经元被沉默。

 

此外,通过使用在谷氨酸存在下发荧光的特定蛋白质,显示EEC在葡萄糖刺激物存在下释放谷氨酸。此外,在谷氨酸受体阻滞剂存在下抑制兴奋性突触后电流。这些研究结果表明EECs使用神经递质谷氨酸快速转导大脑的腔内刺激。

 

除了分泌神经肽外,一些EEC通过释放速效神经递质将信息传递到大脑肠道的信息,研究人员将其称为神经细胞。研究人员解释说,这种机制可能是第一个感知到饭后立即到达肠道的营养素。然后,参与饱腹感的肠道激素将被释放,到达我们的血液循环并通知大脑。

 

总之,这项实验研究首次展示了一种新的感觉机制,通过这种机制,我们的大脑中的食物被我们的大脑感知,而不受肠道激素的影响。此外,研究人员在讨论中强调,这种新发现的途径不仅可以感知肠腔中的营养成分,还可以被病原体利用,并将导致针对与肠 - 脑轴相关的靶向病症的新疗法。

 

随着新的“神经细胞”的发现,该研究表明,在先前已知的神经元和内分泌途径如何与携带感觉信号到大脑的神经进行通信方面有更密切的关系。

 

您可以在这里看到杜克大学的视频,总结这些新发现。

 

A new enteroendocrine cell type mediates how gut and brain exchange signals from nutrients

22 NOV 2018 | Andreu Prados

Gut Brain Axis, Gut Microbiota, Research & Practice

Tagged: Gut microbiota Gut-brain axis

It has long been known that the gut communicates with the brain via different pathways that include neuronal activation, the release of hormones and immune signals. Enteroendocrine cells (EECs)—scattered along the gastrointestinal tract between absorptive enterocytes—are involved in sensing luminal nutrients and bacteria and communicating this indirectly to the brain via the release of gut hormones (e.g. cholecystokinin). However, the underlying mechanisms that mediate the transduction of gut signals to the brain remain unidentified.

 

A new study, led by Dr. Diego V. Bohórquez from the departments of Medicine and Neurobiology at Duke University (North Carolina, USA), has demonstrated that a type of enteroendocrine cell in the gut layer called the neuropod cell communicates with sensory nerve fibers through direct cell-nerve contact.

 

In order to trace the circuit between EECs and nerves in vivo, the researchers used a modified fluorescent rabies virus that selectively infects EECs and spreads through synapses onto nerves. The virus, given to mice via enema, spread not only to sensory neurons in the colon, but also to vagal neurons projecting into the nucleus tractus solitarius of the brainstem. These findings show the existence of a neuroepithelial circuit that links the intestinal lumen with the brainstem with only one synapse.

 

On the other hand, the neuroepithelial circuit was reconstituted in vitro by coculturing single EECs with sensory neurons to test whether sugar was sensed by the vagus nerve directly or via EECs. Vagal neurons cultured alone did not respond to the glucose stimulus. In contrast, when the sensory neurons were cocultured with EECs, visible connections between the two cell types were made and glucose stimulated action potentials in the neurons.

 

Using optogenetics—a technique that uses flashes of light to monitor the activities of specific individual cells in genetically engineered animals—the researchers discovered both in vitro and in vivo that, in the presence of a photostimulus, glucose elicited excitatory postsynaptic currents as fast as 60ms in light-sensitive EECs. However, a light-inhibitory channel abolished glucose-stimulated activity in the vagal neurons in the presence of a photostimulus. These data show that EECs are required to rapidly transduce a glucose stimulus from gut to sensory neurons.

 

The existence of this gut-brain neural connection capable of rapidly transducing sensory signals from the gut to the brain was indeed supported by previous data. Other researchers had shown that hypothalamic neurons involved in the central control of feeding and energy expenditure were silenced within seconds of nutrients reaching the intestine.

 

Furthermore, by using a specific protein that fluoresces in the presence of glutamate, EECs were shown to release glutamate in the presence of a glucose stimulus. In addition, excitatory postsynaptic currents were suppressed in the presence of glutamate receptor blockers. These findings show that the neurotransmitter glutamate is used by EECs to rapidly transduce luminal stimuli to the brain.

 

A new enteroendocrine cell type mediates how gut and brain exchange signals from nutrients - Gut Microbiota for Health  https://www.gutmicrobiotaforhealth.com/en/a-new-enteroendocrine-cell-type-mediates-how-gut-and-brain-exchange-signals-from-nutrients/