当你的肠道细菌说话时,你的大脑会倾听和回应
When Your Gut Bacteria Talk, Your Brain Listens and Replies
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2019-12-08 21:31
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火星译客

When your gut bacteria talk, your brain listens and replies

当你的肠道细菌说话时,你的大脑会倾听和回应

It’s a conversation, one that may alter immune response and disease progression

这是一个可以改变免疫反应和疾病进展的对话

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Neuroscience

神经系统科学

Neuroscience

洛杉矶生物医学

August 21, 2019

2019年8月21日

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The jury’s still out on how the brain really works. But Sarkis Mazmanian, a medical microbiologist at Caltech, thinks the answers to many of the questions we still have about the brain may actually lie further south — in the gut, where trillions of bacteria live. There, these “good” bacteria live peacefully, helping us to break down fiber and absorb nutrients. They are referred to collectively as the gut microbiome. Despite the presence of the blood-brain-barrier (BBB), a tightly regulated border between the brain and circulating blood, the gut and the brain are in constant communication, either through incoming and outgoing nerves, or through small molecules that can pass through the BBB. Remarkably, many of these molecules are not produced by the human body — they’re made by the bacteria in our microbiome.

大脑究竟是如何工作的,目前尚无定论。但是加州理工学院的医学微生物学家Sarkis Mazmanian认为,我们对大脑的许多疑问的答案实际上可能在更靠南的地方——肠道里,那里生活着数以万亿计的细菌。在那里,这些“好”细菌平静地生活着,帮助我们分解纤维,吸收营养。它们被统称为肠道微生物群。尽管存在血脑屏障(BBB),即大脑和血液循环之间的一个受到严格监管的边界,但肠道和大脑通过传入和传出神经,或通过可以穿过血脑屏障的小分子,保持着持续的交流。值得注意的是,这些分子中有许多不是由人体产生的——它们是由我们微生物群落中的细菌产生的。
 

The composition of our gut microbiome is often thought to be established as we pass through the birth canal, and greatly modified through our immediate environment in the first few years of life. After that, the microbiome becomes largely resistant to new bacteria. Interpreting this “gut-brain” axis has been the focus of Mazmanian’s work, revealing complex interactions between the gut and the brain, which increasingly look connected to everything from thoughts and emotions, to potentially the onset of certain brain disorders including Autism Spectrum Disorder and Parkinson’s disease.

我们的肠道微生物群落的成分通常被认为是在我们通过产道时形成的,并在生命的最初几年里通过我们接触的环境发生了很大的变化。在此之后,微生物群落对新的细菌产生了很大的抵抗力。解释这个“内脏-大脑”轴线一直是Mazmanian工作的重点,它揭示了肠道和大脑之间复杂的相互作用,看起来越来越多地与所有事情联系了起来,从思想和情感到某些大脑疾病发病的可能,包括自闭症谱系障碍和帕金森病。
 

Bacteroides fragilis, a common bacteria that occurs in the gut, oblong spheres stained pink.

Bacteroides fragilis

脆弱拟杆菌
 

CDC

疾病预防控制中心

You may be wondering a few things. How do trillions of bacteria establish themselves in our gut in the first place? How do our immune systems differentiate between the bacteria that make up our microbiome, and other harmful bacteria that makes us sick? Mazmanian says, “I think our microbiome, having evolved in the context of the immune system, have learnt to co-op with the immune system.” He adds, “Instead of trying to combat or invade the immune system, they actually engage it.” The good bacteria actually have a vested interest in their hosts being able to selectively attack dangerous bacteria, either because the “good” bacteria may also be harmed, either directly, or indirectly if their hosts perish. So, instead of avoiding immune cells, these beneficial bacteria have developed properties which redirects the immune response in a way that doesn’t cripple it. The “good” bacteria are spared, and the immune system is not prevented from attacking other pathogens. In this way, an amicable symbiosis is achieved, in which the gut microbiome is able to thrive in the warm, moist, nutrient-rich intestines. In fact, research carried out by graduate student Gregory Donaldson in Mazmanian’s lab suggests that one microbe in particular, called Bacteroides fragilis, might have even achieved long-term stability in the gut because of an immune response involving an antibody called IgA, which actually helps anchor it to the gut wall.

你可能会想知道一些事情。数万亿细菌是如何在我们的肠道中扎根的呢?我们的免疫系统如何区分构成我们微生物群系的细菌和其他让我们生病的有害细菌?Mazmanian说:“我认为我们的微生物群是在免疫系统的环境下进化的,已经学会了与免疫系统合作。”他补充说,“他们不是试图对抗或入侵免疫系统,而是真正地参与其中。”事实上,有益细菌在它们的宿主能够有选择性地攻击危险细菌上有既得利益,因为如果它们的宿主死亡,“有益”细菌也可能受到直接或间接的伤害。因此,这些有益细菌并没有避开免疫细胞,而是发展出了一种特性,在不削弱免疫反应的情况下,重新引导免疫反应。“好”细菌得以幸免,而免疫系统也无法阻止其攻击其他病原体。通过这种方式,一种友好的共生关系得以实现,肠道菌群得以在温暖、潮湿、营养丰富的肠道中茁壮成长。事实上,研究生 Gregory Donaldson在Mazmanian的实验室进行的研究表明,尤其一种被称为脆弱拟杆菌的微生物甚至可能在肠道中获得了长期的稳定性,这是由于一种涉及IgA抗体的免疫反应,这种抗体实际上帮助它固定在肠壁上。
 

Mazmanian believes that our microbiome may influence many diseases. A few years ago, Mazmanian and his group noticed that children with autism — a neuropsychiatric disorder where children suffer from behavioral deficits, such as decreased vocalisation and social interaction, as well as repetitive behavior — also experience digestive issues, such as abdominal cramps and bloating. This was a clue that bacteria could be involved in the disease process. Other clues were that risk factors for autism include having a caesarean section, formula feeding, and taking antibiotics in childhood, all of which change the microbiome.

Mazmanian认为,我们的微生物群落可能会影响许多疾病。几年前,Mazmanian和他的团队注意到患有自闭症的儿童也会出现消化问题,比如腹部绞痛和腹胀——自闭症是一种神经精神病学上的疾病,儿童会出现行为缺陷,比如发声能力和社交能力下降,以及重复性行为——这是细菌可能参与疾病过程的一个线索。其他的线索是自闭症的危险因素包括剖腹产,配方奶喂养,儿童时期服用抗生素,所有这些都改变了微生物群。
 

Mazmanian thinks the same may be true of Parkinson’s disease, a neurodegenerative disorder where neurons in the brain die, leading to motor symptoms like tremors, difficultly in walking, and rigidity. Like with autism, Parkinson’s patients often have gut symptoms. Strikingly, 80 percent of the three million people in the U.S. that suffer from Parkinson’s disease also suffer constipation—symptoms that sometimes precede the onset of motor symptoms. Interestingly, people who have had their vagus nerve, a potential highway between the gut and the brain, removed during surgery, are less likely to develop Parkinson’s disease.

Mazmanian认为同样的道理也适用于帕金森病,这是一种神经退行性疾病,大脑中的神经元会死亡,导致运动症状,如震颤、行走困难和僵硬。与自闭症患者一样,帕金森患者通常也有肠道症状。引人注目的是,在美国300万帕金森病患者中,80%的人还会出现便秘症状——这种症状有时会先于运动症状出现。有趣的是,那些在手术中切除了迷走神经的人患帕金森病的可能性更小,而迷走神经是连接肠道和大脑的潜在通道。
 

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To study how the gut may influence neurological diseases, Mazmanian completely removed the gut microbiome of mice that are genetically engineered to develop autism or Parkinson’s. He found these mice no longer exhibited symptoms of Parkinson’s or autism, suggesting that the microbiome is involved in both diseases. Mazmanian had stumbled on a remarkable discovery. “When we made these germ-free sterile mice, it gave us a research tool that we can now use for other purposes.” Next, he took fecal samples (which contain intact microbiomes of their donors), from both Parkinson’s patients and healthy controls. He put these samples into bacteria-free sterile mice genetically modified to over-express a protein called α-synuclein (αSyn, which is associated with Parkinson’s disease). The mice implanted with microbiomes from people who had Parkinson’s had much worse symptoms than the mice who received microbiomes from a healthy control. Similarly, when mice with autistic behaviors that had their microbiomes removed were given certain beneficial bacteria recovered from neurotypical humans , Mazmanian’s team were able to reduce their vocalisation deficits and repetitive behaviors.

为了研究肠道是如何影响神经系统疾病的,Mazmanian完全清除了那些通过基因工程患上自闭症或帕金森病的老鼠的肠道微生物群。他发现这些老鼠不再表现出帕金森病或自闭症的症状,这表明微生物群与这两种疾病有关。Mazmanian偶然间有了一个意义非凡的发现。“当我们制造这些无菌老鼠时,它给了我们一个研究工具,我们现在可以把它用于其他目的。”接下来,他从帕金森患者和健康对照组中提取粪便样本(其中包含捐赠者体内完整的微生物群落)。他把这些样本注入通过基因改造使得α-synuclein蛋白(αSyn,与帕金森病相关)过度表达的无菌老鼠身上。植入了来自帕金森病患者的微生物群的老鼠比从健康对照组移植微生物群的老鼠有更严重的症状。同样地,当去除有自闭症行为的老鼠体内的微生物群,再给它们注入某些从正常人类身上回收的有益细菌后,Mazmanian的团队就能够减少它们的发声缺陷和重复性行为。
 

By targeting the microbiome, in a personalized way, he hopes to develop a viable therapeutic.

通过以一种个性化的方式瞄准微生物群,他希望开发出一种可行的治疗方法。

Of course, these studies have only been carried out in mice, since there are ethical issues with replacing a healthy human’s microbiome with one from a Parkinson’s patient. However, Mazmanian says that dozens of papers have shown that the gut microbiome in autistic people and Parkinson’s patients are different. The cause of these differences — maybe ethnicity, geography, genetics or diet — is unclear, but Mazmanian’s mouse experiments have led him to a provocative hypothesis. He thinks some forms of autism and Parkinson’s may not arise in the brain at all, but in the gut. By targeting the microbiome, in a personalized way, he hopes to develop a viable therapeutic.

当然,这些研究只在老鼠身上进行过,因为用帕金森病患者体内的微生物群替换健康人类的微生物群存在伦理问题。然而,Mazmanian说,数十篇论文表明,自闭症患者和帕金森病患者的肠道微生物群(与常人)是不同的。造成这些差异的原因——可能是种族、地理、遗传或饮食——尚不清楚,但Mazmanian的老鼠实验让他提出了一个颇具争议性的假设。他认为,某些形式的自闭症和帕金森病可能根本不是在大脑中产生的,而是在肠道中产生的。通过以一种个性化的方式瞄准微生物群,他希望开发出一种可行的治疗方法。
 

It’s not just the gut that sends signals to the brain. Weirdly, the brain also communicates with the gut, although understanding this process has been more challenging. Members of Mazmanian’s lab have been trying to better understand brain --> gut communication by working with neuroscientists using genetic engineering techniques, brain lesion studies, and studying the vagus nerve. Anecdotally, we rely on “gut-feelings” or “gut-instincts” to help us make decisions, sometimes we experience “gut-reactions” in response to an experience, and when we are overcome with anxiety or excitement, we often feel it in in our gut as a stomach-ache or “butterflies.” These turns of phrase suggest what these scientists suspect: that our brains send signals to our gut via our nervous system in response to queues in the environment.

不仅仅是肠道向大脑发送信号。奇怪的是,大脑也在和肠道交流,尽管理解这个过程更具挑战性。Mazmanian实验室的成员一直试图通过与神经科学家合作,利用基因工程技术、大脑损伤研究和迷走神经来更好地理解大脑到肠道的交流。有趣的是,我们依靠“肠子感觉”或“肠子直觉”来帮助我们做决定,有时我们会经历对某一经历的“肠子反应”,当我们克服焦虑或兴奋时,我们经常会感到胃疼或“紧张”。这些措辞暗示了这些科学家的猜测:我们的大脑通过我们的神经系统向我们的肠道发送信号,以对环境中的队列做出反应。

“Someday, you and I may go to the doctor and be prescribed a pill with a live bacteria inside of it as the remedy.”

“有一天,可能你我去看医生时,医生会开给我们一粒含有活细菌的药丸治病。”
 

Mazmanian’s lab are trying to not just identify the bacteria that inhabit our guts, but what these bacteria are doing. “We take a reductionist approach in the fact that we work with single organisms we can genetically manipulate,” he says. “I want to manipulate both the bacteria and the host,” isolating each on a molecular level to identify the mechanisms by which they work.

Mazmanian的实验室不仅试图识别我们肠道内的细菌,还试图了解这些细菌在做什么。“我们采取的是一种简化的方法,因为我们研究的是可以对其进行基因操作的单一有机体,”他说,“我想同时控制细菌和宿主,”在分子水平上分离两者以确定它们的运作机制。
 

Conversely, Mazmanian likens many traditional drug treatments to pouring oil all over the engine of a car, in the hope that some might get into the right place. He thinks the future of medicine is in “drugs from bugs,” saying, “Someday, you and I may go to the doctor and be prescribed a pill with a live bacteria inside of it as the remedy.”

相反,Mazmanian把许多传统的药物疗法比作把油倒在汽车的引擎上,并希望其中一些疗法能找对地方。他认为医学的未来在于“来自虫子的药物”,他说,“有一天,可能你我去看医生时,医生会开给我们一粒含有活细菌的药丸治病。”

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