How the Gut Microbiota Influences Our Health and How We Can Influence It

ABSTRACT 摘要

“众所周知，人类肠道里的微生物，也被称为肠道菌群，在我们感觉如何以及我们是否健康或患病中起一定的作用。在大多数情况下，微生物是如何调节身体健康的仍是一个未知数，而通过调控微生物群来改善人们的身体健康的方法也才刚刚开始应用。在这篇文章里，我们将解释如何研究肠道菌群、我们已经了解到的肠道菌群是如何影响身体健康的，以及已经在使用的或正在研究的方法去影响微生物，以改善人体的健康。”

The microbes in the human gut, also known as the gut microbiota, are known to play a part in how we feel and whether we are healthy or sick. How the microbiota regulates health is still unknown in most cases, and medical treatments to manipulate the microbiota to improve people’s health are only just starting to be used. In this article, we explain how the gut microbiota is currently studied, what we already understand about how the gut microbiota influences health, and ways that are already used, or are being investigated, to influence the microbiota to improve health.

肠道菌群：螺母和螺栓

THE GUT MICROBIOTA: NUTS AND BOLTS

它们在你的身体内，在你身上，是你身体的一部分...它们是微生物！微生物是微小到我们用眼睛无法直接看到的生物体。在我们身体内部和体表上，有着数量大致和人体细胞一样多的微生物。微生物已经在人类体内聚居了数百万年，与我们共同进化。在这漫长的相互联系中，我们与微生物变得相互依赖：我们为微生物提供食物以及它们生活的场所，微生物则反过来为我们服务。我们才开始了解微生物对我们的诸多影响，但有一些令人感到惊讶的例子：它们帮助我们消化食物、训练我们的免疫系统以保护我们免受感染、调节我们的食欲，甚至影响到我们是否感到开心或悲伤。我们身体内的微生物大多数生活在肠道里，肠道是你---宿主---与微生物的最大的相互作用点之一。我们把生活在肠道里的所有微生物集合称为“肠道菌群”。

They are in you, they are on you, they are a part of you … they are microbes! Microbes are organisms so small that we cannot see them with our eyes. On and inside our bodies, we have roughly as many microbes as human cells. Microbes have been colonizing humans for millions of years, and we have evolved together. During this long association, we became dependent on each other: we offer the microbes food and a place to live, and in turn they work for us. We are only beginning to understand the many effects microbes have on us, but there are some surprising examples: they help us digest food, train our immune systems, protect us from infections, regulate our appetites, and even influence whether we feel happy or sad. Most of the microbes in our bodies live in the gut, which is one of the largest interfaces between you—the host—and the microbes. We call the entire collection of microbes living in the gut the gut microbiota.

生活在肠道里的微生物皆不相同。到目前为止，研究人员已经鉴别了超过2000种生活在人类体内或体表的不同微生物物种。每个人的肠道菌群在物种的数量以及丰裕度上都各不相同，这使得每个人的微生物群都是独一无二的。

The microbes in the gut are not all the same. So far, researchers have identified more than 2,000 different species of microbes that live in or on humans. Everyone differs in the number and abundance of species in the gut microbiota, which makes the microbiota of each person unique.

肠道菌群从何而来？在婴儿还未出生前，生活在他们体内或体表的微生物少之甚少。出生时，人类宝宝会与一些微生物朋友第一次相遇，随着年龄的增长，他们将接触新的微生物。儿童的微生物群与成年的微生物群是迥然不同的，直至成年，微生物的物种数量都会稳步增加。即使在成年人里，微生物群的组成部分仍可以发生改变，这取决于我们的基因、我们所处的环境以及我们所吃的食物。

Where does the gut microbiota come from? There are few microbes living in or on babies before they are born. At birth, human babies meet some microbial friends for the first time, and they continue picking up new microbes as they grow older. The microbiota of children looks different from that of adults, and the number of species increases steadily until adulthood (Figure 1). Even in adults, the composition of the microbiota can still change it and depends on our genes, the environment we live in, and the foods we eat.

图1-肠道菌群随着我们年龄的增长而变化

Figure 1 - The gut microbiota changes as we age.

（A）在新生儿时期，肠道内的微生物少之甚少。随着孩子的长大，他或她会从其他人或环境中获取微生物，以形成肠道菌群。

(A) In newborns, very few microbes are present in the gut. As a child grows older, he or she picks up microbes from other people or the environment, which form the gut microbiota. 

（B，C）肠道菌群会随着时间的推移而变得更加多样化。每个人体内微生物的确切组合是独一无二的，因此每个人的微生物群看起来都不一样。

(B,C) The gut microbiota changes and gets more diverse over time. The exact mix of microbes in every person is unique, and therefore everyone’s microbiota looks different.

健康的肠道菌群是什么呢？

WHAT IS A HEALTHY GUT MICROBIOTA?

我们知道拥有一个健康的肠道菌群尤为重要。但健康的肠道菌群是什么呢？尽管许多科学家正竭尽全力地解答这个问题，但要回答这个问题还可谓难上加难。人与人之间，甚至在同一个人身体里，微生物物种的数量以及这些物种的相对丰度是不同的，而且也会随着时间的推移而变化。此外，体内环境的变化可以将一些微生物物种由无害的居住者变为危险的入侵者。因此，每当肠道中的某些东西发生变化时，数以百计的其他东西也会随之发生改变，这就使科学家们极难理解这些变化中哪些才是最重要的。

We know that a healthy gut microbiota is important. But what is a healthy microbiota? This is an extremely difficult question to answer, even though many scientists are working hard on solving it. The number of different species and the relative abundances of these species vary between people and even within the same person over time. In addition, changes in the bodily environment can turn some microbiota species from harmless inhabitants into dangerous invaders. As a result, every time something changes in the gut, hundreds of other things change as well, which makes it extremely difficult for scientists to understand which of these changes is actually important.

科学家们是如何研究如此错综复杂的系统呢？其中一个方法就是利用老鼠，这些老鼠是在特别干净的条件下培养的，这样它们就没有任何微生物群，但它们依然是健康的。科学家们给这些老鼠一些从患病的或健康的人体内分离出来的肠道菌群。如果只是接收了“病人”微生物群的小鼠患病，我们便知道这个疾病是由该微生物群引起的，因为这是老鼠间唯一的区别。知道这个非常重要，但在大多数情况下，我们仍然不理解这是如何发生的。

How do scientists study the function of such a complex system? One way is to use mice that are raised in exceptionally clean conditions, so that they do not have any microbiota, but they are still healthy. Scientists give these mice some of the gut microbiota isolated from either sick or healthy humans. If only the mouse given the “sick” microbiota develops the disease, we know the disease is due to the microbiota, because it is the only difference between the mice. This is important to know, but in most cases, we still do not understand how this happens.

肠道菌群是如何维持我们健康的？

HOW THE GUT MICROBIOTA CAN KEEP US HEALTHY

在某些情况下，我们拥有微生物是如何影响我们的相关解释。其中一种情况是其与免疫系统的相互作用。肠道里的免疫系统需要防止有危害的微生物免遭其造成疾病。但它不应该对正常的微生物群做出过度反应。免疫系统通过产生平衡的激活信号和停用信号来实现这种状态。如果平衡被打破，产生的大多数是激活信号，就会导致疾病。科学家们发现，微生物群释放出的一种被称为“丁酸盐”的废物，可以指示免疫系统制造更多的停用信号，因此，微生物群有助于维持这种平衡，防止免疫系统过度反应。

In some cases, we have explanations for how the microbiota affects us. One such case is its interaction with the immune system. The immune system in the gut needs to prevent dangerous microbes from causing disease, but it should not over-react to the normal microbiota. The immune system achieves this state by producing a balance of activating and de-activating signals. If the balance is disturbed and mostly activating signals are produced, disease can result. Scientists have discovered that a waste product released by the microbiota, called butyrate, can instruct the immune system to make more deactivating signals. The microbiota thus helps keep the balance and prevents the immune system from overreacting [1].

第二种情况是微生物群在预防肠道感染中的作用。如果你吃的食物或饮用的水中含有能让人致病的微生物（沙门氏菌可能是你曾听说过的这样一种微生物），实际上在大多数情况下你仍保持健康。这往往是由于你的肠道菌群可以通过产生能够杀害入侵者的物质直接与它们对抗，通过刺激你的免疫系统增强你对有害细菌的抵抗力，通过消耗掉所有可供的食物使得留给侵入者的食物几近于无。

A second case in which we have some understanding of how the microbiota affects us is the role of the microbiota in preventing gut infections. If you eat food or drink water containing microbes that can make you sick (Salmonella is one such microbe that you might have heard of), in many cases you actually stay healthy. This is often due to your gut microbiota, which can directly fight the invaders by producing substances that can harm them, by stimulating your immune system to increase your resistance to harmful bacteria, and by consuming all the available food so nothing is left for the invaders [2].

第三种情况是微生物群从我们的食物中采集能量所扮演的角色。你是否曾听说过膳食纤维这个词？膳食纤维富含在蔬菜水果中，含有大量的能量。但这些能量不能被我们身体所利用，因为我们没有提取它们的机器。然而，肠道菌群就有这台机器，微生物群可以消化膳食纤维，释放一些能量供我们利用。在这种情况下，你的微生物群会生产出你每天利用的能量的10%。如果在食物不充裕的情况下，这是生存的一个重要要素，但如果周围的食物太多，这个过程会潜在地导致人变胖。

A third case is the role of the microbiota in harvesting energy from our food. Have you heard the term dietary fiber? Dietary fiber is abundant in fruits and vegetables, and it contains a lot of energy. But this energy cannot be used by our bodies because we do not have the machinery to extract it. However, the gut microbiota has this machinery, and the microbes can digest dietary fiber, releasing some of the energy for us to use. In this way, your microbiota produces 10% of the total energy that you use every day [3]. This is an important factor for survival if there is not enough food, but if there is too much food around, this process can potentially contribute to people becoming overweight.

调控肠道菌群的方式

WAYS TO MANIPULATE THE GUT MICROBIOTA

一个健康的微生物群对我们身体的一些主要功能十分重要。但即便我们的肠道菌群是健康的，像有危害的细菌的入侵事件或抗生素的使用都可以剧烈地改变它。在某些情况下，肠道菌群的这些变化可导致疾病。

在过去的十年里，人们已经发现了保持一个健康的微生物群或调控微生物的组成部分的方法。还有一些有助于促进特有微生物和抑制已知的有危害的微生物的干预措施。以下是诸如此类的三种干预措施。（参见图2）

A healthy gut microbiota is important for some of the main functions of our bodies. But even if our microbiota is healthy, events like the invasion of dangerous bacteria or the use of antibiotics can dramatically change it. In some cases, these changes to the gut microbiota can cause diseases.

In the last decades, ways to help us keep a healthy microbiota or to manipulate the microbiota’s composition have been discovered. There are also interventions that help to promote specific beneficial microbes and to inhibit ones known to be dangerous. Here are three such interventions (also see Figure 2).

图2-操控肠道菌群以改善健康

Figure 2 - Manipulating the gut microbiota to improve health.

（A）益生元是食物中可以专门喂养希望得到的微生物的养分。有益的微生物就会在肠道内增加，从而改变微生物群，有望消除不需要的微生物。

(A) Prebiotics are components of food that can specifically feed desired microbes. The beneficial microbes will then increase in the gut, which will change the microbiota, hopefully eliminating the undesired microbes. 

（B）粪菌移植将健康人的肠道菌群转移到病人的肠道中。这些移植可以很好地治疗一种叫艰难梭菌的有危害的细菌的感染。

(B) Fecal microbiota transplants put a healthy person’s gut microbiota into a sick person’s gut. These transplants can work well for treating infections with a dangerous bacterium called C. difficile.

（C）针对微生物群中单一类型的微生物进行疫苗接种，可以训练免疫系统产生针对这种微生物的抗体，从而帮助身体排出不希望得到的微生物。

 (C) Vaccination against a single type of microbe in the microbiota can train the immune system to make antibodies against this microbe, which helps the body to flush out the undesired microbes.

益生元 Prebiotics

不同的微生物对食物的偏好各不相同。维持有益微生物生计的其中一种方式是通过给它们提供它们最爱吃的食物来帮助它们生长。这些它们喜爱的膳食纤维物质被称为“益生元”。例如，有些种类的有益细菌喜欢吃某种类型的膳食纤维。要想理解它，我们可以把它想像成一场赛车比赛，不同类型的车所需的燃料种类各不相同。食用益生菌就像只给你想赢的汽车提供燃料（有益细菌），而不给其他细菌提供燃料。

Different microbes have different food preferences. One way of supporting beneficial microbes is to help them grow by providing them with the foods they like best [4]. These preferred dietary substances are called prebiotics. For example, some species of beneficial bacteria like to eat a certain kind of dietary fiber. One way to think about this would be as a car race, with different cars needing different kinds of fuel. Eating prebiotics is like giving fuel only to the cars you want to win (the beneficial bacteria), while not fueling the others.

粪便移植Fecal Transplantation

改变微生物群的另一种方式是将一个健康人（捐赠者）的肠道菌群转移到病人（接收者）体内。这种方式被称为“粪菌移植”，你可以联想一下，它就像把一支踢得不好的足球队换成另一支球队一样。粪菌移植是从捐赠者的粪便中提取出肠道菌群，通过吞服药片或经过鼻子或直肠的管状器官将其转移到接收者的肠道里。你不觉得这很吸引人吗?这是可以理解的反应!然而，对于一种疾病，粪菌移植似乎十分有用：艰难梭状芽孢杆菌（简称：艰难梭菌）的反复感染。如果肠道菌群受到干扰，这种杆菌就会茁壮生长，从而导致严重的疾病。艰难梭菌可通过抗生素将其消灭，但它们对抗生素耐药性十分普遍，通常来说当病人停止服用抗生素时，疾病就会复发。粪菌移植可治愈80%～90%遭受此疾病的人，通常而言是安全的。然而，粪菌移植常常以一种不可预见的方式影响接收者的肠道菌群。

Another way to change the microbiota is the transfer of the gut microbiota from a healthy person (the donor) to a sick one (the recipient). This is called a fecal microbial transplant, and you can think about it like replacing a soccer team that does not play well together with a different team. A fecal microbial transplant is done by taking the donor’s gut microbiota from their feces, and transferring it into the recipient’s gut, either by swallowing a pill or via a tube through the nose or the rectum. Does not sound very appealing to you? A very understandable reaction! However, for one disease, fecal microbial transplants seem to work extremely well: recurrent infections with Clostridioides difficile, a microbe that can thrive if the gut microbiota is disturbed, causing a very serious disease. C. difficile can be killed by antibiotics, but antibiotic resistance is common, and often the disease comes back when the patient stops taking the antibiotics. Fecal microbial transplants cure 80–90% of people suffering from this disease and they are generally believed to be safe. However, fecal microbial transplantation often influences the recipient’s gut microbiota in an unpredictable way.

精密微生物群工程 Precision Microbiota Engineering

当前的研究聚焦在更有针对性地改变微生物群，以避免粪菌移植中的一些不可预测性。一种可能是针对特定的不需要的微生物进行口服疫苗接种。和其他大多数疫苗一样，口服疫苗会告诉免疫系统制造出一系列被称为抗体的蛋白质，它可以黏在目标微生物上。这些抗体将这些微生物黏成一团，使得更容易将其从肠道中清除。为了促进这个过程，我们可尝试使用另一个技巧：一种与疫苗所针对的微生物非常相似，但又无害的微生物，这种微生物可以与疫苗一起服用。这种微生物被称为利基竞争者。利基竞争者会使难以对付的微生物的生活变得更加艰难，因为它会与那些微生物竞争食物和生存空间。设想一下，这就像在玩抢座椅游戏一样：免疫系统与目标微生物保持距离，谁的速度更快、适应性更好，谁就能取代它们的位置。这种策略显示出了前途无量的结果，目前正对其进行研究，以使其能广泛运用。

Current research focuses on more targeted changes to the microbiota, to avoid some of the unpredictability of fecal microbial transplants. One possibility is oral vaccination against specific unwanted microbes. Like most other vaccines, oral vaccination tells the immune system to make proteins called antibodies that stick to the targeted microbes. These antibodies glue these microbes together into large clumps, which are easier to flush out of the gut [5]. To help this process, we can use another trick: a microbe that is very similar to the one targeted by the vaccine, but not harmful, can be given with the vaccine. This microbe is called a niche competitor. The niche competitor makes life even harder for the problematic microbe because it competes with the problematic microbe for food and living space. Imagine this like playing musical chairs: the immune system keeps the targeted microbes at distance and whoever is faster and better adapted can take their place. This strategy shows promising results, and research is underway to make it broadly usable.

带回家的信息（总结）

TAKE-HOME MESSAGE

我们才刚刚开始了解肠道菌群影响你的健康的方式，但我们已经知道了它有着强有力的影响，以及可以用巧妙的方法影响它。了解肠道菌群的作用是研究中的高度活跃领域。世界各地的团队正努力界定什么样的特性会使微生物群“健康”或“患病”，另一些团队则在继续研发技术，使微生物群发生精确变化。这项研究将进一步揭露人类与微生物之间的复杂关系，并将为改善许多人的健康和生活质量带来更好的方法。

We are only beginning to understand the ways in which the gut microbiota influences your health and well-being, but we already know it has a strong effect and that there are smart ways to influence it. Understanding the role of the gut microbiota is a highly active area of research. As some groups around the world work to define what characteristics make a microbiota “healthy” or “diseased,” others are continuing to develop techniques to make precise changes in the microbiota. This research will shed more light on the complex relationships between humans and microbes, and will lead to better ways for improving the health and quality of life for many people.

Glossary 术语表

Microbes: ↑ All living things that are not visible by the naked eye are called microbes. They are found in most places on earth, and perform important functions in the environment and for our health, but some microbes make us sick.

微生物群：凡是肉眼看不到的生物都叫微生物。它们可在地球上大多数地方被发现，它们在环境中发挥着重要的功能，对我们的健康也有重要的作用，但有些微生物会让我们生病。

Gut Microbiota: ↑ The community of microbes that lives in our digestive tract, one of the densest microbial communities on the planet.

肠道菌群：生活在我们消化道中的微生物群落，是地球上最密集的微生物群落之一。

肠道菌群：

Prebiotics: ↑ Components in food that specifically feed beneficial members of the gut microbiota, to promote them over other species.

益生元：食物中专门喂养肠道微生物群有益成员的组成成分，以促进它们（在数量上）超过其他物种。

Fecal Microbial Transplant: ↑ The transfer of the gut microbiota in the feces of a healthy person to a person with a disturbed gut microbiota. This technique is currently used for treating recurrent C. difficile infections.

粪菌移植：将健康人粪便中的肠道微生物群转移到肠道微生物群受到干扰的人身上。这种技术目前用于治疗艰难梭菌的周期性感染。

Oral Vaccination: ↑ Training the immune system to react against specific microbes by swallowing the killed microbe, or parts of the microbe.

口服疫苗：通过吞食被杀死的微生物或部分微生物来训练免疫系统对特定的微生物做出反应。

Niche Competitors: ↑ Members of a biological community that need the same resources (live in the same ecological niche) and are in direct competition for them.

利基竞争者：一个生物群落的成员需要相同的资源(生活在相同的生态位上)，它们会直接竞争这些资源。

原文出处：https://kids.frontiersin.org/articles/10.3389/frym.2021.576428