It can cure diseases, cause diseases, and even "control" people's brains. How do intestinal flora have such powers?

Introduction:

Gut microbes are called the second genome of humans and are closely related to our health. Gut microbes can both treat and cause diseases. When they are disordered, they can induce various diseases. In recent years, probiotic therapy and fecal transplantation have been born, which are closely related to intestinal flora. Therefore, intestinal microbes are one of the hottest research directions in life sciences.

For this topic, we are fortunate to connect with Dr. Wu Meng, a researcher at the University of Washington and a favorite student of Jeffrey Gordon, a leader in the field of intestinal microbes, to share her views on intestinal microbes.

Wu Meng (Researcher at the University of Washington) | Guest

Ye Shuisong | Interview

01 Types of human intestinal microorganisms

Ye Shuisong: Dr. Wu Meng, can you introduce the human microbiome? What are its main categories?

Wu Meng: Gut microbes mainly refer to the microbial community that exists in the human intestine. It is considered the second genome mainly because it has a very large number of genomes, far exceeding the number of genes in humans. At present, we believe that these microorganisms mainly include bacteria, fungi, viruses and other microorganisms.

Escherichia coli

In terms of bacteria, this is the most familiar to us and is also the largest part of the intestinal flora, including the well-known E. coli, but in fact E. coli is only a very small part of the intestinal flora, accounting for less than 1%. Then we usually hear about bifidobacteria and lactic acid bacteria in our daily life, which are also part of the intestinal flora.

But they are not actually the main part of the intestinal flora of healthy adults. The main part of the intestinal flora of healthy adults is Bacteroides and Firmicutes. We may not hear much about these in our daily life, but they are actually the main intestinal flora of normal healthy adults.

We also have some fungi, viruses and other microorganisms in our bodies, which are also part of our intestinal flora.

02 Regulatory role of intestinal microorganisms

Ye Shuisong: In which functions of the body do intestinal microorganisms mainly participate in regulating? What impact do they have on our health?

Wu Meng: We now believe that intestinal flora has four main impacts on our body.

First, intestinal flora participates in our nutrient metabolism and helps us digest some foods that we cannot digest, such as some cellulose. At the same time, it produces some energy and helps us absorb energy. We also believe that it helps us block the invasion of some harmful bacteria, which is related to the competitive relationship between them. Finally, intestinal flora plays a great role in regulating our immune system. In recent years, we have also found that intestinal flora also has a certain regulatory effect on the nervous system.

03 Gut Microbes and the Immune System

Ye Shuisong: As you just said, intestinal microorganisms are closely related to our immune system. Can you tell us how they participate in immune regulation and thus affect our health?

Wu Meng: We still believe that the colonization of the intestinal flora into the human body occurs after birth. The development of the human immune system also occurs after birth, so we usually believe that the 1,000 days after birth is a golden window for the intestinal flora to affect the immune system. During this process, the composition of the intestinal flora itself undergoes a major change, and immune cells also undergo a major differentiation process. Therefore, it affects the development of the immune system by affecting the differentiation of immune cells.

In adults, different components of the intestinal flora also have some regulatory effects on immune cells, which can cause the differentiation of immune cells. Another aspect of its regulation is that it can also produce some metabolites to regulate the immune system.

04 The relationship between intestinal flora and cancer

Ye Shuisong: Professor Wu, the next question is about cancer, which is also one of our current hot research directions. Is the intestinal flora also closely related to the regulation of some cancers?

Wu Meng: Current research suggests that intestinal flora plays a major role in the development and progression of cancer, and a major research hotspot now is that it also plays a major role in the treatment of cancer.

In terms of the development and progression of cancer, let's take colon cancer as an example, because this is also a place where intestinal flora mainly exists. Comparing the flora of patients with colon cancer and normal healthy people, we can find that their composition is very different. Researchers have found that some special bacteria are more related to patients with colon cancer, and then they will use mouse models to further understand what role pathogenic bacteria play in this process.

Another hot topic is immunotherapy. The response or non-response to immunotherapy is also closely related to the intestinal flora, which is also a hot topic on the impact of intestinal flora on cancer.

Ye Shuisong: In the past two years, the therapeutic effects of immune checkpoints PD-1, PD-L1, and CTLA-4 are closely related to intestinal flora, is that right?

Wu Meng: Yes. Around 2015-2016, some articles using mouse models appeared, and they found that the intestinal flora had a great impact on it. Then scientists continued to study in this direction and found that such a phenomenon was also seen in the human body. The simplest comparison is that if you use germ-free mice and give them immunotherapy, most of the germ-free mice will not respond.

This means that we need a bacterial community to regulate our immune system and enable it to create a normal immune environment so that immunotherapy can work.

Because people carry bacteria, some people may use some antibiotics while undergoing immunotherapy, so we may need to minimize the use of antibiotics when using immunotherapy in the future. In addition, some patients who have not used antibiotics may not respond.

We now want to understand whether these non-responses are related to their intestinal flora. If so, can we find new targets or some bacteria to promote its immunotherapy?

05 The impact of oral bacteria on intestinal flora

Ye Shuisong: There are various kinds of bacteria in our mouths. Will they affect the flora in our intestines and then have an impact on our health?

Wu Meng: Our research on COVID-19 patients found that during the course of their disease, whether oral bacteria entering the intestines may cause some health effects is a direction we are currently studying.

It is still unknown what functional impact it will have, but we do have such observations and discoveries. In different disease models, we have found an increase in oral bacteria, and the oral bacteria themselves will have an impact on health through the interaction between the oral cavity and the mucosa.

06 How to maintain the balance of intestinal flora

Ye Shuisong: In our intestines, as you just said, there are many beneficial bacteria, but there are also some pathogenic bacteria. How do the beneficial bacteria and pathogenic bacteria normally compete with each other to maintain a balance, and under what circumstances do they break this balance?

Wu Meng: Generally speaking, these beneficial bacteria basically protect us. For a healthy adult, most of the time, the intestinal flora protects us from being infected by harmful bacteria. This is mainly achieved in two ways.

First, competition for space. Because beneficial bacteria have already occupied most of the surface of our intestines, when harmful bacteria come, they cannot colonize in the intestines.

Second, there is competition for nutrients. If beneficial bacteria have already used up the intestinal nutrients, pathogenic bacteria will not have suitable nutrients and will not be able to survive.

At the same time, these beneficial bacteria can also regulate our immune system, allowing us to better resist harmful bacteria. They themselves also promote the immune system to produce some antimicrobial peptides and some immune cells, which can play a role in resisting harmful bacteria.

Of course, when there are a large number of harmful bacteria, or when these harmful bacteria have discovered some tricks to resist the protection of beneficial bacteria, we may still be infected with harmful bacteria.

Ye Shuisong: That is to say, in our intestines, these beneficial bacteria and harmful bacteria actually exist at the same time. Normally, the beneficial bacteria account for the majority, and they inhibit the proliferation of harmful bacteria, right?

Wu Meng: There are several definitions of harmful bacteria. If we conduct a "census" of the intestinal flora, harmful bacteria are harmful bacteria in the traditional sense, but in fact, most of the time they do not exist in the intestinal flora of normal healthy people.

Of course, we also found some so-called "opportunistic pathogens", which are also present in the intestinal flora of healthy people, but they do not cause any diseases under normal circumstances. However, when there are some changes in the health status of the human body, they may take the opportunity to come out and cause some diseases.

07 How to regulate intestinal flora through diet

Ye Shuisong: Taking weight loss as an example, how do we regulate intestinal flora through diet and achieve the goal of weight loss?

Wu Meng: Because the research in this area is still ongoing, there is no clear medical guideline that diet can be used to regulate intestinal flora for weight loss. I think this is still under research.

However, through current research, we can talk about some basic contents:

First, try to eat high-fiber foods, because these high-fiber foods can provide more nutrition to beneficial bacteria, and some of the metabolites they produce have been proven to be helpful to human health. So this is something you can pay attention to in terms of diet.

Second, pay attention to the diversity of your diet, because in the process of studying intestinal flora, we found that different intestinal flora can digest very different foods.

Third, probiotics and prebiotics. Often, we take probiotics, but if there is no suitable food for them, they may not be able to survive any longer, so we may need to reduce some high-sugar and high-fat foods as much as possible. We also found in our experiments that the nutrients provided by these high-sugar and high-fat foods are more for some potential pathogens, and are not particularly helpful for beneficial bacteria.

08 Research hotspots of intestinal flora

Ye Shuisong: Your previous laboratory has done very well in the field of intestinal microorganisms and is at the international leading level. Can you tell us about our current understanding of the intestines, and what difficulties and hot directions need to be overcome in the future?

Wu Meng: I think the intestinal flora has made a great breakthrough. Many studies have proved the important role of the intestinal flora. However, compared with other studies, we believe that the intestinal flora is still in a very early stage, and there are still many different issues that need our continued research.

First, although we now know that there are some microorganisms in our intestinal flora, we do not have a hard indicator of a healthy person's intestinal flora, such as how to determine whether it is a healthy intestinal flora after measuring it.

Google has also done some work. They have tested the intestinal flora of many people, trying to use big data methods to discover the "most basic intestinal flora" of humans. This intestinal flora is what we really understand as a normal and healthy intestinal flora. This is a direction that needs to be studied.

Second, the molecular mechanism relationship between the intestinal flora and the host is still the focus of many laboratories. Because only when we truly understand how the intestinal flora interacts with our host can we truly utilize this intestinal flora.

Third, the intestinal flora is greatly affected by the environment. We just talked about how food can have a great impact on the intestinal flora. In fact, emotions and various diets can have a great impact on the intestinal flora. How these environmental factors affect the intestinal flora is also a research focus.

09 Side effects of antibiotics

Ye Shuisong: There is a lot of abuse of antibiotics in our country at present. What impact will it have on intestinal microorganisms?

Wu Meng: If antibiotics are not used according to a normal course of treatment, they will selectively affect bacteria before they kill them, making them resistant to the drugs. This is the reason why many pathogens emerge, and it is the consequence of the abuse of antibiotics.

Another thing is that the use of antibiotics will affect the intestinal flora and kill some beneficial bacteria in the intestinal flora, so it may also cause flora disorders and lead to some diseases.

If a doctor prescribes antibiotics, you should use them according to the amount specified by the doctor, instead of thinking that you can stop using them because you are already well. You should use antibiotics according to the doctor's instructions.

Ye Shuisong: In our daily life and diet, what suggestions do you have for everyone to maintain a steady state of intestinal flora or a good intestinal flora?

Wu Meng: I think diet is very important first. Try to eat high-fiber foods, and diverse foods are very helpful to intestinal flora.

Then you can try to reduce the intake of high-sugar and high-fat foods.

On the other hand, we should not over-clean and frequently use disinfectants and antiseptic products such as hand sanitizers. If the environment is a relatively normal and clean one, it doesn't matter if there are many bacteria around us. Intestinal flora will also be affected by some rhythms, so normal sleep and maintaining a good mood will help the intestinal flora.

This article is a work supported by Science Popularization China Starry Sky Project

Team/Author: Deep Science

Reviewer: Wang Qiang, deputy chief physician of the Department of Gastroenterology, Peking Union Medical College Hospital

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.