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GABA太大，无法穿过血脑屏障进入大脑，血脑屏障是一种细胞防御墙，限制了可以从血管进入大脑的分子的大小和类型。然而，该分子可以通过迷走神经或肠内分泌细胞起作用。一些研究人员可能会质疑为什么细菌比增强GABA的药物更有益。但是斯特兰德维兹说，这种细菌可能不仅仅是简单地增强GABA。他指出，它们产生的分子可能会对大脑和身体产生其他影响，从而解决抑郁症的其他症状。
一位科学家表示：如果我们能证明一种效应，并且没有任何的副作用，那么久没有理由不去进行临床实验。
在Holobiome，Strandwitz及其同事鉴定并排名了30种有应用前景的GABA产生细菌，其中包括Gilbert正在测试的细菌。现在，该公司正在招募外部制造商，以找出哪种产生GABA的细菌最适合大量生产以供人体测试。研究人员希望及时完成法规和道德审查，以便在2021年初开始进行人体试验。“我们之所以能够取得如此进展，是因为我们了解微生物学，” Strandwitz说。最开始的目标是用于失眠和肠易激综合征便秘。
最终，Holobiome还是不知道其最佳产品是单个的细菌、一个菌群还是由细菌合成的化合物。 Strandwitz说:“就目前而言，活着的微生物的效果最好。”他认为，一个包含比典型益生菌种类更广的细菌群将更具有通用性，能够治疗抑郁症等多种疾病。
HOLOBIOME已经将目光投向了能产生GABA以外的肠道微生物。数千种新分离出的微生物在公司总部的冷冻瓶中等待着被发掘出它们作为精神药物的潜能。最近加入Holobiome的Stephen Skolnick说:“每当我们看到有人发表关于微生物组的新论文，我们就可以检查是否有这些细菌并复制该实验。”
这些实验的一个关键工具是“肠道模拟器”，这是一系列由管道连接的烧瓶，有几个入口用于添加微生物和监测肠道内发生的情况。通过允许模拟微生物组从细菌的不同组合中发展而来，有时还有混合的哺乳动物细胞，研究人员可以研究新分离出的微生物及其产物。如果科学家们看到了希望，他们可以迅速转向思考开发的与其相关的产品。
GABA is too big to reach the brain by slipping across the blood-brain barrier, a cellular defense wall that limits the size and types of molecules that can get into the brain from blood vessels. Instead, the molecule may act through the vagus nerve or the enteroendocrine cells. Some researchers might question why bacteria would be any more beneficial than GABA-boosting drugs. But Strandwitz says the bacteria may do more than simply boost GABA. He notes that they produce molecules that may have other effects on the brain and body, thereby addressing other symptoms of depression.
He and Gilbert are unfazed by those uncertainties. “If we can show an influence, without any side effects, I don’t see any reason for not going forward with clinical trials,” Gilbert says.
At Holobiome, Strandwitz and colleagues have identified and ranked 30 promising GABA-producing bacteria, including the ones Gilbert is testing. Now, the company is enlisting an outside manufacturer to figure out which GABA-producing bacteria are best suited to produce in large enough quantities to test in people. The researchers hope to complete regulatory and ethical reviews in time to start human trials by early 2021. “We’ve been able to progress at this rate because we know our microbiology,” Strandwitz says. The initial target conditions are insomnia and irritable bowel syndrome with constipation.
Ultimately, Holobiome does not know whether its best products will be a single bacterial species, a group of species, or a compound made by bacteria. “For now, live bugs work the best,” Strandwitz says. He suggests a consortium of bacteria that includes a wider range of species than typical probiotics will be more versatile and able to treat multiple aspects of, say, depression.
HOLOBIOME IS ALREADY LOOKING beyond GABA producers. Thousands of newly isolated microbes wait in frozen vials at the company’s headquarters for their psychobiotic potential to be explored. “Whenever we see someone publishes a new paper on the microbiome, we can check if we have those bacteria and replicate the experiments,” says Holobiome’s Stephen Skolnick, who recently joined the company.
A key tool for those experiments is a “gut simulator,” a series of flasks connected by tubing, with several portals for adding microbes and for monitoring what’s happening inside. By allowing a mock microbiome to develop from different combinations of bacteria, sometimes with mammalian cells in the mix, the researchers can investigate newly isolated microbes and their products. If the scientists see promise, they can quickly pivot to thinking about additional products to develop.
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