There’s a New Link Between Gut Health and Alzheimer’s Disease
There’s a New Link Between Gut Health and Alzheimer’s Disease
肠道健康与阿尔茨海默病之间存在新的联系
For years, scientists have known that the gut microbiome of people with Alzheimer’s differs from that of healthy people. What remains unclear is whether these differences are a consequence of the disease, contribute to it, or simply accompany it. It is possible that part of the puzzle lies not in the gut bacteria themselves but in the molecules they produce, which end up circulating throughout the body.
多年来，科学家们一直知道阿尔茨海默病患者的肠道微生物群与健康人不同。但尚不清楚的是，这些差异究竟是疾病的结果、诱因，还是仅仅伴随疾病出现。谜题的一部分可能不在于肠道细菌本身，而在于它们产生的分子，这些分子最终会在全身循环。
A team of scientists believes it has found one such molecule. In a study published in Nature Communications, the researchers identified imidazole propionate (ImP)—a compound produced by certain gut bacteria—as a possible link between the microbiome and Alzheimer’s disease.
一个科学家团队认为他们已经发现了一种这样的分子。在发表于《自然-通讯》（Nature Communications）的一项研究中，研究人员确定咪唑丙酸（ImP）——一种由特定肠道细菌产生的化合物——可能是微生物群与阿尔茨海默病之间的联系纽带。
From the Gut to the Brain
从肠道到大脑
The hypothesis put forward by the researchers begins in the gut. Some bacteria use an amino acid called histidine, and by metabolizing it, produce ImP. Some of this molecule can enter the bloodstream and circulate throughout the body.
研究人员提出的假设始于肠道。一些细菌利用一种名为组氨酸（histidine）的氨基酸，通过代谢产生 ImP。这种分子的一部分可以进入血液并在全身循环。
The problem begins at the brain’s border. Experiments in the new study indicate that ImP can weaken the blood-brain barrier, which protects the brain and controls what substances can pass into it via blood. A less effective barrier can help the metabolite enter the brain, where researchers found that it can interact directly with neurons.
问题始于大脑的边界。这项新研究中的实验表明，ImP 会削弱血脑屏障，而血脑屏障负责保护大脑并控制血液中的哪些物质可以进入大脑。屏障功能的减弱有助于这种代谢产物进入大脑，研究人员发现它可以在那里直接与神经元相互作用。
This is where two key players in Alzheimer’s disease come into play: the amyloid beta and tau proteins. In a brain affected by Alzheimer’s, amyloid beta accumulates, forming plaques between neurons. Tau, for its part, undergoes abnormal changes that alter its function and promote the formation of harmful structures within cells. Both phenomena are closely linked to neuronal deterioration and constitute two of the disease’s main biological hallmarks.
这就是阿尔茨海默病中两个关键角色发挥作用的地方：β-淀粉样蛋白（amyloid beta）和 tau 蛋白。在受阿尔茨海默病影响的大脑中，β-淀粉样蛋白会积聚，在神经元之间形成斑块。而 tau 蛋白则会发生异常变化，改变其功能并促进细胞内有害结构的形成。这两种现象都与神经元退化密切相关，构成了该疾病的两个主要生物学标志。
In the experiments, ImP appears to have the ability to exacerbate both. The researchers found that it can promote the accumulation of amyloid beta plaques and increase tau modification through a process known as phosphorylation.
在实验中，ImP 似乎有能力加剧这两种现象。研究人员发现，它可以通过一种称为磷酸化的过程，促进β-淀粉样蛋白斑块的积聚并增加 tau 蛋白的修饰。
The model presented in the study functions as a chain: Certain gut bacteria produce ImP; the metabolite enters the bloodstream; it can compromise the blood-brain barrier and reach the brain; and, once there, it promotes changes related to amyloid beta and tau.
研究中提出的模型像是一条链：特定的肠道细菌产生 ImP；该代谢产物进入血液；它会损害血脑屏障并到达大脑；一旦进入大脑，它就会促进与β-淀粉样蛋白和 tau 蛋白相关的变化。
But just because a biological explanation is coherent doesn’t mean that the entire chain is actually occurring in the human body. To test the extent of this relationship, the researchers first looked for evidence of it in humans and then tested different parts of the mechanism in mice and cells.
但仅仅因为一种生物学解释逻辑通顺，并不意味着整个链条确实在人体内发生。为了验证这种关系的程度，研究人员首先在人类身上寻找证据，然后在小鼠和细胞中测试了该机制的不同部分。
Evidence in Humans and Mice
人类和小鼠身上的证据
The scientists analyzed ImP levels in the blood of 1,196 cognitively healthy adults with a mean age of 61.2 years. Those with higher levels of the metabolite scored, on average, worse on cognitive tests. They also had higher levels of pTau-217—a modified form of the tau protein used as a biomarker for Alzheimer’s—and of NfL, a protein released in greater quantities when neurons are damaged. Both can be measured in the blood and provide clues to changes in the brain even before symptoms appear.
科学家们分析了 1,196 名认知健康的成年人（平均年龄 61.2 岁）血液中的 ImP 水平。那些代谢产物水平较高的人，在认知测试中的平均得分更差。他们的 pTau-217（一种作为阿尔茨海默病生物标志物的 tau 蛋白修饰形式）和 NfL（神经元受损时释放量增加的蛋白质）水平也更高。两者均可在血液中测量，即使在症状出现之前，也能为大脑的变化提供线索。
The researchers also had access to cognitive tests and biomarker measurements taken over time. When comparing people with the highest and lowest levels of ImP, they found that the former group showed faster cognitive decline over time.
研究人员还获得了随时间推移进行的认知测试和生物标志物测量数据。在比较 ImP 水平最高和最低的人群时，他们发现前一组随时间推移表现出更快的认知能力下降。
The researchers administered ImP for months to two groups of mice genetically modified to develop characteristics of Alzheimer’s disease. The results were consistent: The metabolite worsened the signs of the disease. In some animals, amyloid beta plaques increased; in others, tau abnormalities and the reaction of astrocytes—cells involved in protecting and maintaining the brain—worsened.
研究人员给两组经过基因改造以产生阿尔茨海默病特征的小鼠施用了数月的 ImP。结果是一致的：这种代谢产物加剧了疾病的迹象。在一些动物中，β-淀粉样蛋白斑块增加；在另一些动物中，tau 蛋白异常以及星形胶质细胞（参与保护和维持大脑的细胞）的反应恶化。
There Is No “Alzheimer’s Bacterium”
不存在所谓的“阿尔茨海默病细菌”
Several of the bacteria capable of producing ImP can also be found in healthy people.
几种能够产生 ImP 的细菌在健康人体内也能找到。
“ImP-producing bacteria are present in a large fraction of people, but they’re not very abundant in most people,” says Federico Rey, a coauthor of the study and professor of bacteriology at the University of Wisconsin, in a statement. “But something we have learned over the years is that a microbe doesn’t have to be abundant to have an impact on the host.”
“产生 ImP 的细菌存在于很大一部分人群中，但在大多数人中并不丰富，”该研究的合著者、威斯康星大学细菌学教授费德里科·雷（Federico Rey）在一份声明中表示。“但我们多年来学到的一点是，微生物不必非常丰富也能对宿主产生影响。”
Some bacteria possess the machinery necessary to produce ImP, but having them in the gut does not necessarily mean that a person will accumulate large amounts of the metabolite. The concentration that ultimately reaches the bloodstream appears to depend on a combination of factors. The researchers found differences related to age, sex, and genetics, while previous studies have also linked ImP production to diet and the composition of the microbiome.
一些细菌拥有产生 ImP 所需的机制，但肠道内存在这些细菌并不一定意味着一个人会积累大量的代谢产物。最终进入血液的浓度似乎取决于多种因素的综合作用。研究人员发现了与年龄、性别和遗传相关的差异，而之前的研究也将 ImP 的产生与饮食和微生物群的组成联系起来。
For the same reason, having bacteria capable of producing ImP does not mean that a person will develop Alzheimer’s disease. Age, genetics, metabolic, and vascular factors, among others, play a role in the risk of developing the disease.
出于同样的原因，拥有能够产生 ImP 的细菌并不意味着一个人一定会患上阿尔茨海默病。年龄、遗传、代谢和血管因素等都在患病风险中发挥作用。
A Drug to Reduce the Risk?
一种降低风险的药物？
While it would seem to make sense to develop a drug that would eliminate or deactivate the microorganisms that produce the molecule, the authors caution that the situation is more complex. These bacteria produce ImP by metabolizing histidine, an essential amino acid that the body needs and that is present in numerous foods, particularly those rich in protein.
虽然开发一种能够消除或灭活产生该分子的微生物的药物似乎很有道理，但作者提醒说，情况更为复杂。这些细菌通过代谢组氨酸产生 ImP，组氨酸是人体必需的一种氨基酸，存在于许多食物中，尤其是富含蛋白质的食物中。
For the researchers, a more promising approach would be to target ImP itself or the bacterial machinery that produces it. They compare the idea to the treatment of high cholesterol. Just as introducing statins into the body lowers “bad” cholesterol to reduce cardiovascular risk, an inhibitor capable of reducing the concentration of ImP in the blood could one day be developed.
对于研究人员来说，一种更有前景的方法是针对 ImP 本身或产生它的细菌机制。他们将这一想法比作高胆固醇的治疗。正如引入他汀类药物可以降低“坏”胆固醇以减少心血管风险一样，未来或许可以开发出一种能够降低血液中 ImP 浓度的抑制剂。
This story originally appeared on WIRED en Español and has been translated from Spanish. 本文最初发表于《连线》西班牙语版（WIRED en Español），由西班牙语翻译而来。