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Ten years ago, the researcher Phil Strandwitz was giving a talk at Harvard University regarding a new paper discussing a potential link between the gut microbiome and the developing brain. In particular, he wanted to highlight how a small group of scientists were examining whether the gut may play a role in autism spectrum disorder..

十年前，研究人员Phil Strandwitz在哈佛大学发表了一篇关于讨论肠道微生物组与发育中的大脑之间潜在联系的新论文。特别是，他想强调一小部分科学家正在研究肠道是否可能在自闭症谱系障碍中发挥作用。。

“There was somebody in the front row who just slammed their book shut and said, ‘This is impossible, microbes can’t influence the brain,” remembers Strandwitz, now CEO of Cambridge, Massachusetts-based biotech Holobiome. “Now, if you go to any neuroscience conference there are almost always microbiologists there.”.

“最前面有人刚刚敲打他们的书关闭并说，'这是不可能的，微生物无法影响大脑'，”马萨诸塞州剑桥生物技术全生物组首席执行官Strandwitz记得。“现在，如果你去参加任何神经科学会议，那里几乎总是有微生物学家。”。

While the connection between the gut and the central nervous system was once considered speculative, prestigious journals like Science are now publishing papers on how gut microbes can influence the brain and behavior.

虽然肠道和中枢神经系统之间的联系曾经被认为是推测性的，但像科学这样的着名期刊现在正在发表关于肠道微生物如何影响大脑和行为的论文。

In 2019, academics at the Weizmann Institute of Science in Israel published a landmark study in Nature where they showed that the gut microbiome may affect the course of the incurable neurodegenerative disease amyotrophic lateral sclerosis (ALS). Disease progression in mice, whose genomes had been altered to create an ALS-like illness, slowed after they received either certain strains of gut microbes or metabolites known to be secreted by those microbes.

2019年，以色列魏茨曼科学研究所的学者在自然界发表了一项具有里程碑意义的研究，他们发现肠道微生物组可能影响无法治愈的神经退行性疾病肌萎缩侧索硬化症（ALS）的病程。小鼠的疾病进展，其基因组已被改变以产生ALS样疾病，在它们接受已知由这些微生物分泌的某些肠道微生物菌株或代谢物后减慢。

Further studies have followed, linking the microbiome to other neurological diseases and disorders..

随后进行了进一步的研究，将微生物组与其他神经系统疾病和病症联系起来。。

“There’s a really good chance that the connectivity between our microbes and us could explain, at least in some cases, depression, symptoms of Parkinson’s, recovery from stroke, pain and even risk of dementia, a wide range of different things that are classically considered neurological in origin,” says Strandwitz..

“我们的微生物和我们之间的联系很有可能解释，至少在某些情况下，抑郁症，帕金森病症状，中风恢复，疼痛甚至痴呆症的风险，这些都是经典的各种不同的东西Strandwitz说。。

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Understanding The Gut/Brain Axis

了解肠/脑轴

At the simplest level, we now know that microbes in the intestines can communicate directly with the CNS through the vagus nerve, which senses activity throughout the gastrointestinal (GI) tract and runs from the gut to the brain. Through this connection they may be capable of modulating neuroinflammation as well as the levels of neuroactive molecules such as neurotransmitters and neuropeptides which drive complex behaviors relating to emotions and anxiety..

在最简单的层面上，我们现在知道肠道中的微生物可以通过迷走神经直接与中枢神经系统沟通，迷走神经可以感知整个胃肠道（GI）的活动，并从肠道到大脑。通过这种联系，它们可能能够调节神经炎症以及神经活性分子（如神经递质和神经肽）的水平，从而驱动与情绪和焦虑有关的复杂行为。。

In addition, Strandwitz says that microbes continuously produce proteins and other molecules which are absorbed into the bloodstream, where they can influence the localized immune system and the peripheral nervous system. According to John Cryan, a professor and microbiome researcher at University College Cork, some of these microbial metabolites may also play a role in regulating the blood-brain barrier, the thin layer of cells that separates the brain from the periphery.

此外，Strandwitz说，微生物不断产生蛋白质和其他分子，这些分子被吸收到血液中，在那里它们可以影响局部免疫系统和周围神经系统。科克大学教授兼微生物组研究员约翰·克莱恩（John Cryan）表示，这些微生物代谢产物中的一些也可能在调节血脑屏障方面发挥作用，血脑屏障是将大脑与周围分离的薄层细胞。

A more permeable blood-brain barrier would allow toxins and other infections to reach the brain, potentially contributing to some neurodegenerative disorders..

更具渗透性的血脑屏障将使毒素和其他感染到达大脑，可能导致某些神经退行性疾病。。

“Right now, there’s a lot of interest in how the microbiome could shape the integrity of the blood-brain barrier, which could have implications for many disorders from Alzheimer’s to epilepsy,” says Cryan. “For epilepsy, anything that changes the balance between inhibition and excitation could be playing a role, which is why the microbiome could be involved.”.

Cryan说：“目前，人们对微生物组如何影响血脑屏障的完整性非常感兴趣，这可能会影响从阿尔茨海默氏症到癫痫的许多疾病。”。“对于癫痫，任何改变抑制和兴奋之间平衡的东西都可能发挥作用，这就是微生物组可能参与的原因。”。

The most successful non-pharmacological treatment for epilepsy has long been the ketogenic diet and in recent years research has begun to suggest that the diet’s renowned anti-seizure effects are in fact mediated by the microbiome.

癫痫最成功的非药物治疗长期以来一直是生酮饮食，近年来研究已经开始表明饮食中着名的抗癫痫作用实际上是由微生物组介导的。

Now San Diego-based biotech Bloom Science, which has received an investment from my team at Leaps, has developed a new oral therapeutic that aims to replicate the antiepileptic effects of the ketogenic diet in children with Dravet syndrome, a rare form of epilepsy. The therapeutic contains two gut microbes which have been found in both cell-based assays and animal studies to reduce neuronal hyperexcitability, which increases risk of seizures, and increase the levels of a neurotransmitter called gamma aminobutyric acid (GABA) in the hippocampus.

现在，位于圣地亚哥的生物技术Bloom Science已经获得了我团队的快速投资，开发了一种新的口服治疗药物，旨在复制生酮饮食对Dravet综合征（一种罕见的癫痫形式）儿童的抗癫痫作用。该治疗剂含有两种肠道微生物，这些微生物已在基于细胞的测定和动物研究中发现，以减少神经元过度兴奋，这增加了癫痫发作的风险，并增加了海马中称为γ-氨基丁酸（GABA）的神经递质的水平。

Low levels of GABA are also linked to seizures..

低水平的GABA也与癫痫发作有关。。

Through boosting GABA and modulating other key bioenergetic pathways, the hope is that this intervention can significantly reduce seizure frequency and duration, and perhaps even eliminate seizures. Last month, Bloom announced positive results from a Phase 1 safety trial in healthy adult volunteers which showed that it was well tolerated with no serious adverse events.

通过促进GABA和调节其他关键的生物能量途径，希望这种干预可以显着减少癫痫发作的频率和持续时间，甚至可以消除癫痫发作。上个月，Bloom宣布健康成人志愿者进行的1期安全性试验取得了积极成果，结果表明该试验耐受性良好，无严重不良事件发生。

The company has since received Rare Pediatric Disease Designation for this oral therapeutic from the FDA for Dravet syndrome and intends to progress to a Phase 2 clinical trial next year..

此后，该公司已从FDA获得Dravet综合征口服治疗药物的罕见儿科疾病名称，并打算明年进入2期临床试验。。

Bloom is also investigating whether this same oral therapeutic can offer clinical benefits for patients with ALS through addressing the underlying oxidative stress that is a critical factor in the progression of the disease. Preclinical studies using mouse models of ALS have shown that this therapeutic can attenuate motor neuron loss as well as increase lifespan and motor coordination in these mice.

Bloom还正在研究这种相同的口服治疗药物是否可以通过解决潜在的氧化应激来为ALS患者提供临床益处，氧化应激是疾病进展的关键因素。使用ALS小鼠模型的临床前研究表明，这种治疗剂可以减轻运动神经元的损失，并延长这些小鼠的寿命和运动协调性。

The company intends to conduct a Phase 2 clinical trial in ALS patients next year. Future plans also include developing microbiome-based therapies to address anxiety and depression..

该公司打算明年在ALS患者中进行2期临床试验。未来的计划还包括开发基于微生物组的疗法来解决焦虑和抑郁。。

Alleviating Symptoms of Autism Spectrum Disorder

缓解自闭症谱系障碍的症状

One of the first microbiome-targeting drugs that may become clinically available for a neurological condition could be a therapy aimed at treating ASD-associated irritability, which can include aggression, severe tantrums, or the need for isolation.

可能临床上可用于神经病症的第一种微生物组靶向药物之一可以是旨在治疗ASD相关易怒的疗法，其可以包括攻击性，严重发脾气或需要分离。

Autistic children have long been known to have differences in their gut microbiota and as a result are more susceptible to GI issues compared with their neurotypical peers. According to Stew Campbell, CEO of Woburn, Massachusetts-based Axial Therapeutics, irritability in children with ASD represents a considerable unmet need and is thought to be exacerbated by these underlying differences in the gut..

人们早就知道自闭症儿童的肠道微生物群存在差异，因此与他们的神经型同龄人相比，他们更容易受到胃肠道问题的影响。根据马萨诸塞州Woburn轴向治疗公司首席执行官Stew Campbell的说法，ASD儿童的烦躁不安代表了相当大的未满足需求，并且被认为会因肠道中的这些潜在差异而加剧。。

Last year, a team of researchers led by Axial Therapeutics’ scientific founder, professor Sarkis Mazmanian at California Institute of Technology, demonstrated in mice how bacteria-derived metabolites in the gut can reach the brain via the bloodstream and alter communication networks associated with anxious behavior..

去年，由Axial Therapeutics的科学创始人，加利福尼亚理工学院的Sarkis Mazmanian教授领导的一组研究人员在小鼠身上展示了肠道中细菌衍生的代谢物如何通过血流到达大脑并改变与焦虑相关的沟通网络行为。。

The company has developed an experimental product they describe as a tasteless and odorless powder formulation that can be mixed with soft food and taken orally. It is designed to bind to these metabolites in the gut before they can get into circulation. Right now, the product is in a Phase 2b study conducted across multiple centers in the United States, Australia and New Zealand, with data anticipated to be reported in the first quarter of 2024..

该公司开发了一种实验产品，他们将其描述为无味无味的粉末配方，可以与软食混合并口服。它被设计成在它们进入循环之前与肠道中的这些代谢物结合。目前，该产品正在美国，澳大利亚和新西兰多个中心进行的2b期研究中，预计数据将在2024年第一季度报告。。

The Size Challenge

尺寸挑战

Yet there are still considerable challenges. According to Nik Sharma, CEO of London-based biotech BioCorteX, one of the major ones when it comes to potentially using the gut microbiome to alter the path of neurological disorders, is its sheer size.

然而仍然存在相当大的挑战。根据伦敦生物技术BioCorteX首席执行官Nik Sharma的说法，在潜在地利用肠道微生物组改变神经系统疾病的路径方面，其主要规模之一就是其庞大的规模。

“The numbers [of microbes] are astronomical,” says Sharma. “It’s probably not going to be one individual species of bacteria which is driving any of these diseases, it’s probably going to be a consequence of the interactions between millions of microbes.”

Sharma说：“微生物的数量是天文数字。”。“可能不是一种驱动任何这些疾病的细菌，这可能是数百万微生物之间相互作用的结果。”

BioCorteX are now looking to apply mathematical modelling to better understand how a particular therapeutic might impact the entire ecosystem of microbial species within the gut, with the aim of yielding insights that could improve the design of future drugs.

BioCorteX现在正在寻求应用数学建模来更好地理解特定治疗剂如何影响肠道内微生物物种的整个生态系统，目的是产生可以改进未来药物设计的见解。

“We don't just look at the bacteria, but also viruses and fungi in the gut, and they all interact to some extent,” says Sharma. “This is important to model because for example you could try to medicate with a bacteria, but that bacteria isn’t going to do very well if surrounding phages - viruses which attack a particular species of bacteria - act to keep it in check.”.

Sharma说：“我们不仅要看细菌，还要看肠道中的病毒和真菌，它们都在一定程度上相互作用。”。“这对建模很重要，因为例如你可以尝试用细菌进行药物治疗，但如果周围的噬菌体-攻击特定细菌种类的病毒-起到控制作用，细菌就不会做得很好。”。

As the science advances, I am optimistic that targeting the microbiome will provide a novel way of tackling some of the most devastating neurodegenerative conditions.

随着科学的进步，我乐观地认为，针对微生物组将提供一种解决一些最具破坏性的神经退行性疾病的新方法。

Sharma is particularly passionate about trying to make an impact in the field of ALS. “That’s my specialist clinical area and it’s a terrible disease,” he says. “We know that the gut microbiome is intimately connected with the microglia, brain cells which are detrimental later on in the process of these neurodegenerative diseases.

Sharma特别热衷于试图在ALS领域产生影响。他说：“这是我的专科临床领域，这是一种可怕的疾病。”。“我们知道肠道微生物组与小胶质细胞密切相关，脑细胞在这些神经退行性疾病的过程中后来是有害的。

There’s a lot of hurdles to overcome before we can do this, but I think that connection between the microbiome and those microglia will be an attractive target to go after.”.

在我们做到这一点之前还有很多障碍需要克服，但我认为微生物组和小胶质细胞之间的联系将成为一个有吸引力的目标。

Thank you to David Cox for additional research and reporting on this article. I’m the head of Leaps by Bayer, the impact investment arm of Bayer AG. We invest in teams pursuing fundamental breakthroughs in life science, targeting ten huge challenges or “leaps” facing humanity, including to protect brain and mind..

感谢David Cox对本文的更多研究和报道。我是拜耳公司的影响力投资部门拜耳的飞跃之首。我们投资于追求生命科学根本突破的团队，针对人类面临的十大挑战或“飞跃”，包括保护大脑和心灵。。