| 幸福大叔 |
2022-07-03 18:47 |
gut-brain? 大肠脑你懂吗?
A scientist explores the mysteries of the gut-brain connection
Dec 6, 2017 / Karen Frances Eng
The brain in your head and the one in your gut are always exchanging info. But how do they do it? Neuroscientist Diego Bohórquez is trying to find out the answers.
If you were asked where the human body’s nervous system is located, you’d probably answer “the brain” or “the spinal cord.” But besides the central nervous system, which consists of those two organs, our bodies also contain the enteric nervous system, a two-layer lining with more than 100 million nerve cells that spans our guts from the esophagus to the rectum. The enteric nervous system has been called “the second brain,” and it’s in constant contact with the one in our skull. That’s why just thinking about food can lead your stomach to start secreting enzymes, or why giving a speech can lead to your feeling queasy.
Until recently, scientists thought the two systems communicated solely via hormones produced by enteroendocrine cells scattered throughout the gut’s lining. After sensing food or bacteria, the cells release molecular messengers that prompt the nervous system to modulate behavior. But it turns out the process may be much more direct. Intriguingly, Duke University gut-brain neuroscientist Diego Bohórquez, a TED Fellow, has found that some enteroendocrine cells also make physical contact with the enteric nervous system, forming synapses with nerves. This revelation opens the door to rethinking how we might affect these signals — and might someday change how we treat conditions as varied as obesity, anorexia, irritable bowel syndrome, autism and PTSD.
What fueled Bohórquez’s interest in the gut-brain connection? Chickens. After he moved to the US from Ecuador, his first position was as a visiting research scholar at North Carolina State University, where he worked in a nutrition laboratory that focused on chickens. “In poultry production, the biggest challenge is to feed the hatchling chicks as soon as possible so the bird can achieve its maximum growth potential,” Bohórquez says. “My PhD advisor came up with the idea to feed the chicks in the egg before they hatch. This in-ovo feeding consisted of delivering enzymes into the amniotic fluid of the embryo right before it hatched.” Bohórquez was surprised at how this practice changed what the chicks did after they hatched. “The unfed chickens came out of the egg and slept for five or six hours. But the ones fed in ovo went straight to eat,” he says. “They were also more alert, spent time looking around, and pecked each other. I became intrigued about how ingested nutrients alter behavior.”
A friend’s gastric bypass surgery also fueled his curiosity. “A friend was struggling with obesity and, as a last resort, decided to have gastric bypass surgery. It worked. She lost a lot of weight, and it resolved her diabetes,” he recalls. “But most strikingly, her perception of taste changed. She used to be repulsed by the sight of runny egg yolks, but after the surgery, she craved them.” Such a change in taste has been well documented in some patients who’ve undergone bariatric surgery, but scientists aren’t sure how or why it happens, says Bohórquez. “It’s a new subject, but rewiring the gut appears to physically change how we perceive the taste of food in the brain.”
While scientists have known that nutrients are sensed in the gut by enteroendocrine cells, the exact way this happens was murky. They understood that when stimulated, enteroendocrine cells release hormones that either enter the bloodstream or activate nearby nerves to affect how we eat. “My focus has been to figure out how a sensory signal from a nutrient is transformed into an electrical signal that alters behavior,” Bohórquez says. He and his colleagues began taking a close look at enteroendocrine cells, using 3D electron microscopy. Imaging them in this way revealed a whole new structure that hadn’t been seen before. “It turns out enteroendocrine cells not only have microvilli, or tiny protrusions, exposed to the gut, but they also have a foot-like extension, which we called the neuropod,” says Bohórquez. “It became evident that enteroendocrine cells have similar physical attributes to neurons, so we wondered whether they might be wired to neurons, too.”
The secret to tracking synaptic connections: a special kind of rabies. The key to illuminating the process was inserting a tiny amount of modified fluorescent rabies virus into the colon of a mouse. “Rabies is a virus that infects neurons and spreads through synaptic connections, so when used in a modified form that only allows it to jump one neuron at a time, it’s useful for tracking neural circuits,” Bohórquez explains. Seven days after undergoing this procedure, the enteroendocrine cells of the mouse colon glowed green, offering evidence that the sensor cells were indeed behaving as neurons. Bohórquez then bred a mouse that would allow the tracking rabies to make a second jump. When he delivered the tracking rabies into the colon of this new mouse, the enteroendocrine cells and the nerves that they connected to lit up, demonstrating the existence of a physical synapse between the sensor cells and its nervous system — and a physical connection that hadn’t been seen before.
Charting the communication pathway between the gut and brain could someday lead us to new treatments for disorders and conditions. A number of diseases — autism, obesity, anorexia, irritable bowel syndrome, inflammatory bowel disease, PTSD and chronic stress — share a symptom known as altered visceral sensing, or a hyper- or hyposensitivity to gut stimuli. “For instance, clinical observations have suggested that some children with anorexia may be hyper-aware of the food they ingest from an early age,” says Bohórquez. “Under normal circumstances, this process happens without detailed spatial and temporal awareness, but those children can feel what’s going on in there, which triggers anxious feelings.” With this knowledge, scientists may better understand other disorders that have been thought to be solely psychological.
Can our enteroendocrine cells smell, taste and touch? They possess the same molecular receptors that enable mechanical, chemical and thermal sensing in your nose and mouth, says Bohórquez. “These mechanisms are just beginning to be studied, and it’s where research is headed.” And beyond the gut, he points out, the lining of our body’s organs — including our lungs, prostate and vagina — all possess sensor cells similar to enteroendocrine cells. “Future exploration will continue to uncover how the brain perceives signals from these organs and how they affect how we feel,” he says.
ABOUT THE AUTHOR
Karen Frances Eng is a contributing writer to TED.com, dedicated to covering the feats of the wondrous TED Fellows. Her launchpad is located in Cambridge, UK.
你头脑中的大脑和你肠道中的大脑总是在交换信息。但是他们是怎么做到的呢？神经科学家 Diego Bohórquez 正试图找出答案。
如果有人问你人体的神经系统在哪里，你可能会回答“大脑”或“脊髓”。但除了由这两个器官组成的中枢神经系统外，我们的身体还包含肠神经系统，这是一个由超过 1 亿个神经细胞组成的两层内衬，从食道到直肠跨越我们的肠道。肠神经系统被称为“第二个大脑”，它与我们头骨中的那个不断接触。这就是为什么一想到食物就会让你的胃开始分泌酶，或者为什么发表演讲会让你感到恶心。
直到最近，科学家们还认为这两个系统仅通过散布在肠道内壁的肠内分泌细胞产生的激素进行交流。在感知食物或细菌后，细胞会释放分子信使，促使神经系统调节行为。但事实证明，这个过程可能要直接得多。有趣的是，杜克大学肠脑神经科学家、TED 研究员 Diego Bohórquez 发现，一些肠内分泌细胞也与肠神经系统发生物理接触，与神经形成突触。这一发现为重新思考我们如何影响这些信号打开了大门——并且有朝一日可能会改变我们对待肥胖、厌食症、肠易激综合征、自闭症和创伤后应激障碍等各种疾病的方式。
是什么激发了 Bohórquez 对肠脑连接的兴趣？鸡。从厄瓜多尔移居美国后，他的第一个职位是在北卡罗来纳州立大学担任访问研究学者，在一家专注于鸡的营养实验室工作。 “在家禽生产中，最大的挑战是尽快喂养刚孵化的小鸡，这样小鸟才能发挥其最大的生长潜力，”Bohórquez 说。 “我的博士生导师提出了在小鸡孵化之前喂它们鸡蛋的想法。这种卵内喂养包括在胚胎孵化前将酶输送到胚胎的羊水中。” Bohórquez 对这种做法如何改变了小鸡孵化后的行为感到惊讶。 “没吃饱的鸡从蛋里出来，睡了五六个小时。但那些用鸡蛋喂食的就直接吃了，”他说。 “他们也更加警觉，花时间环顾四周，互相啄食。我对摄入的营养素如何改变行为产生了兴趣。”
一位朋友的胃绕道手术也激发了他的好奇心。 “一位朋友正在与肥胖作斗争，作为最后的手段，他决定进行胃绕道手术。有效。她减轻了很多体重，这解决了她的糖尿病，”他回忆道。 “但最引人注目的是，她对品味的看法发生了变化。她曾经对流淌的蛋黄感到厌恶，但在手术后，她很想吃。” Bohórquez 说，在一些接受过减肥手术的患者中，这种口味的变化已经得到了充分的证明，但科学家们不确定它是如何发生或为什么发生的。 “这是一个新课题，但重新连接肠道似乎会在物理上改变我们对大脑中食物味道的感知方式。”
虽然科学家们已经知道肠内分泌细胞可以在肠道中感知营养物质，但这种情况发生的确切方式尚不清楚。他们了解到，当受到刺激时，肠内分泌细胞会释放激素，这些激素要么进入血液，要么激活附近的神经，从而影响我们的饮食方式。 “我的重点是弄清楚来自营养素的感觉信号如何转化为改变行为的电信号，”Bohórquez 说。他和他的同事开始使用 3D 电子显微镜仔细观察肠内分泌细胞。以这种方式对它们进行成像揭示了一个以前从未见过的全新结构。 “事实证明，肠内分泌细胞不仅具有暴露于肠道的微绒毛或微小突起，而且它们还具有脚状延伸，我们称之为神经足，”Bohórquez 说。 “很明显，肠内分泌细胞具有与神经元相似的物理属性，因此我们想知道它们是否也可能与神经元相连。”
追踪突触连接的秘密：一种特殊的狂犬病。阐明这一过程的关键是将少量改良的荧光狂犬病病毒插入小鼠的结肠。 “狂犬病是一种感染神经元并通过突触连接传播的病毒，因此当以一次只允许其跳跃一个神经元的修改形式使用时，它可用于跟踪神经回路，”Bohórquez 解释说。接受此程序 7 天后，小鼠结肠的肠内分泌细胞发出绿色光，证明传感器细胞确实表现得像神经元。 Bohórquez 然后培育了一只老鼠，可以让追踪狂犬病进行第二次跳跃。当他将追踪狂犬病病毒送入这只新老鼠的结肠时，肠内分泌细胞
并且它们连接的神经亮起，表明传感器细胞与其神经系统之间存在物理突触 - 以及以前从未见过的物理连接。
绘制肠道和大脑之间的沟通路径，有朝一日可能会引导我们找到治疗疾病和病症的新方法。许多疾病——自闭症、肥胖症、厌食症、肠易激综合征、炎症性肠病、创伤后应激障碍和慢性压力——都有一种被称为内脏感觉改变或对肠道刺激过敏或过敏的症状。 “例如，临床观察表明，一些患有厌食症的儿童可能从小就对他们摄入的食物非常敏感，”Bohórquez 说。 “在正常情况下，这个过程是在没有详细的空间和时间意识的情况下发生的，但那些孩子可以感觉到那里发生了什么，这会引发焦虑的感觉。”有了这些知识，科学家们可能会更好地理解其他被认为仅仅是心理的疾病。
我们的肠内分泌细胞能闻、尝、摸吗？ Bohórquez 说，它们拥有相同的分子受体，可以在您的鼻子和嘴巴中进行机械、化学和热感应。 “这些机制才刚刚开始研究，这是研究的方向。”他指出，除了肠道之外，我们身体器官的内层——包括我们的肺、前列腺和阴道——都拥有类似于肠内分泌细胞的传感器细胞。 “未来的探索将继续揭示大脑如何感知来自这些器官的信号以及它们如何影响我们的感受，”他说。
关于作者
Karen Frances Eng 是 TED.com 的特约作家，致力于报道奇妙的 TED 研究员的壮举。她的发射台位于英国剑桥。
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