Martin J. Blaser 2018-01-04
时长:22:45 审校:蓝灿辉
《消失的微生物》作者Martin J. Blaser 教授在上海纵论肠之道,并给中国妈妈们提出7点建议!

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Thank you very much, Mr. Gut, I'm very happy to be here. It was very nice to meet so many people today who are interested in my book.And I hope to tell you something that I think is important.

I'm very happy to be here in China, because China, as you know, is in the middle of different kinds of revolutions. And I first came here about 30 years ago, and it is amazing to see how much China has become modern, and ultra-modern.

Today I was on the train, and it's so much nicer than our trains. So we have very much to learn from you, and now maybe I can try to tell you some things as well.




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So today I talk about our missing microbes.

And another way to look at this is that it's a story about ecology, about human ecology and how human ecology is changing.

I was lucky that I have a wonderful publisher, Hunan books, and they have submitted my book, Missing Microbes, and it just won a big award this year.

You can see that people all over the world are reading it, even in Chinese. And because it's being translated into a number of languages, and I'm very pleased that people in China will be able to read it.





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So now let me begin.

And I begin by showing these photographs of Greenland from outer space in 1992 and 2002.

And you can see that in 2002 there is less ice. And the reason that there's less ice is what we call global warming. And we can define global warming as a change in our macro-ecology because of human activities.



And what I'd like to talk about today is how our micro-ecology is changing because of human activities.

And unfortunately, I think it is happening on the same scale, and maybe even a little faster.



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So I will begin by telling you some things about the United States, some things that many of you know already.


This slide behind me is about the trends in obesity in adults in the United States. 

And there are three maps here. The first map is from 1989, and in that year there is no state in the United States where more than 14% of adults are obese. And the last map is from 2010, and at that time there is no state that has less than 20% obesity.



And so what's remarkable is that it's happening all over the country, and the difference between the first and the last map is only 21 years. 

Something very powerful is happening.



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We know that obesity in adults begins in childhood.

And this is illustrated by this slide, looking at obesity trends over about a 35-year period. And you can see that over time, the trends are going up, even in the youngest children.

 In fact, this is happening all over the world. And childhood obesity will one day lead to adult obesity.




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Now it is especially important to think about what's happening in China.

In 1985, there were very few children who were obese, and by 2014 the numbers have skyrocketed.



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In fact, in boys in China, you're almost at the same rate as boys in the United States, and I think that's very bad news. And the trend shows no sign of getting any better.


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Not just children. We're seeing it throughout our society, and I show this just to remind you.

In fact, it's happening to our pets, to our dogs and cats also. But obesity is not the only disease that is going up.



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Now we see big rises in juvenile diabetes, type-1 diabetes. It's doubling every 20 or 25 years.

And asthma is going up everywhere. And diseases of the esophagus are rising dramatically.

And there are many others.



And the question is, why are all these diseases going up at the same time? Do they all have separate causes or is there one thing that is underlying all of them?


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So in Missing Microbes, I talk about the idea that it's because of a change in our microbes, that it is underlying everything.

And that can be illustrated by this slide which is a sketch of the interactions between microbes that know our human biology.



And this is from work I did with a mathematician, Denise Kirchner. 

Our idea is that the microbes are talking to the cells of the human body and is receiving conversations back. And this forms an equilibrium. 

And Denise has shown that this is a very strong equilibrium, it's robust, it's resilient.

这是我和数学家 Denise Kirchner 一起合作得到的成果。


Denise 已经表明这是一个很强大的平衡,它既稳健又有弹性。

What I want to talk about today is what happens when we lose that relationship? What happens when it's.. Firstly when it's disturbed? And then, ultimately, what happens when it's lost?


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So to introduce the subject in another way, let me remind you that we humans are mammals.

And we begin our life in the womb, which is sterile. 

Our big exposure to bacteria, to other microbes, happens when the water breaks, and the baby descends through the birth canal and is covered by the mom's microbes. 

The baby swallows the microbes, and now they have contact with the mother's skin, with the mother's breast. The mothers are kissing and licking babies. All of these are very efficient ways of transferring microbes from one generation to the next.

That's the way it's always been for mammals, for the last 100 million years.






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But these days, mothers are not the same as they used to be. They live in a world of antisepsis. They've taken many courses of antibiotics. They're eating foods that have antibacterials. And babies aren't the same either. They may be born by cesarean section.

Here in Shanghai, about one baby out of two is born by cesarean section. They're missing that first exposure to their mothers' microbes. They're bathed extensively. They're given formula which is only superficially like human milk.

And of course, babies are getting a lot of antibiotics.




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Because of this, over the last 20 years I've been thinking of an idea that I call the disappearing microbiota theory.

And it has two main ideas.

The first is that human ecology is changing, and it has altered the transmission of these microbes, and their maintenance of our very ancestral microbes. 

And that affects the composition of what we're carrying. And especially important are the microbes that are usually acquired early in life, in childhood, since they affect a critical stage in development.





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A few years ago, we extended this idea, and it's shown here, the effect of the mother's status of the microbiota of the next generation.

Our idea of ancient mothers is that they had ancient microbes.And if, before the next generation was born, they lost a few, maybe they could regain them horizontally.But if they lost them and they couldn't regain them, then the next generation would be born at a deficit. And so on, and so forth.

So that the change in each generation is cumulativeIt's not that it resets with each generation, but that it gets worse with each generation. This was our idea.




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And fortunately, there's now evidence supporting this idea.

We talk about helicobacter pylori, which used to be the most common organism, the most important organism in the human stomach.

And here in this study of three generations in Japan, you can see the same kind of step down that we were worried about. 




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We can look at the overall diversity of microbes in the human body.

And this is work by Maria Gloria Dominguez, who's my wife, and she's right there.

Gloria looked at the total amount of diversity in the intestinal tract in children in the United States, and people in Africa and South America.

In a group of uncontacted Amerindians, they had never seen any kind of medical care.

And what she found is that the Amerindians had the greatest diversity. And we people in the United States, had the least. And you can almost imagine that step going down. And comparing the Amerindians to us, it suggests that we have already lost half of our diversity, that it's already gone.


这是我的妻子 Maria Gloria Dominguez 的成果,她今天也在场。

Gloria 调研了美国儿童,以及非洲、南美洲的人们肠道内的物种的总多样性。



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So what could be causing this?

I think there are many causes. But I'm going to highlight just one, and that's antibiotics.

All of us in this room know that antibiotics are one of the greatest discoveries of the 20th century.

There's a picture of Fleming, reenacting the discovery of penicillin. Antibiotics have saved countless lives. They've influenced every area of medicine.




这是一张 Fleming 的照片,重现了青霉素的发现。抗生素挽救了无数人的生命,它们影响了医学的各个领域。

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And as a result, we've been using antibiotics more, and more, and more. How much more?

It's estimated that each year we're using more than 70 billion doses of antibiotics.

That's 10 doses of antibiotics for every man, woman and child on earth.

In the United States, we, on average, we have 833 courses per 1000 population. So that's five courses for every six people, year after year. 

In children under two, they've had almost three courses of antibiotics. By the time they're 10, 10 courses of antibiotics. Pregnant women, just before the transfer of microbes, more than half of them are getting antibiotics.



在美国, 我们每1000人平均使用833疗程的抗生素治疗,也就是每6个人接受5个疗程,年复一年。


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Antibiotic use varies tremendously Doctors. Some doctors prescribe it a lot, some hardly prescribe it.

If we look at the map of the United States, the national average is 833 per 1000. 

In the northeast and the Midwest, it's similar to the average. But in the west, it's much less. In the south it's much more. Between the west and the south, there's a 50% difference, but there's no 50% difference in the rate of serious bacterial infection.

This reflects differences in culture, in practice, not medical necessity.




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So I think it's interesting to compare these two maps from the Center for Disease Control in 2010. On the left, obesity. On the right, antibiotic use.

And if you look at the maps, they look very similar. It's not random.

But these are observational data. They don't tell us anything about cause. Could antibiotics cause obesity? Could obesity cause people to use antibiotics? But they get our attention.





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But in fact, we've known for 70 years that antibiotics affect metabolism.

Because farmers use antibiotics to improve the growth of their livestock. Antibiotics work between chickens and cows, a very wide swath of vertebrate evolution. Antibiotics work as antibacterials, regardless of their chemical structure, their class, their target, their spectrum. Antivirals do not work.Antifungals don't work.

Very importantly, the farmers found that the earlier in life they start the antibiotics, the bigger the effect. And this suggested to us that antibiotics are affecting development.




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So we began to do studies in mice, where we could study it very carefully. Where we would give mice antibiotics or not. Asked what happened to the mice? What happened to their microbiome? And see if we could find relationship.


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I'm going to show you a few of our results. Our first studies were done by Dr. Ilseung Cho when he worked in my lab. He wanted to know what's the effect of antibiotics on body fat.So he gave mice four different antibiotic regimens at the midpoint of the level approved for use on the farm.

And in this graph, you can see that the mice that got antibiotics had more body fat than the control mice that did not get antibiotics. This was our first evidence that antibiotics were changing metabolism in the mice model. And you can see it in these pictures of the mice as well.


我们第一个研究是 Ilseung Cho 博士在我实验室工作期间完成的,他想知道抗生素对体脂有什么影响。他使用了批准用于养殖场的中间剂量,给小鼠制定了四种不同的抗生素方案。


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So this work was continued by Laurie Cox when she was a graduate student in my lab.

She asked what happens if she combined a diet that's high in fat, high in calories, with antibiotics. Would there be additive effects? So she gave mice penicillin, or not.And then, at week 17, half the mice were put on a high-fat diet. She used the same kind of antibiotic regimen that farmers use.

这项工作后来由我实验室的研究生 Laurie Cox 继续推进。


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So in the mice that were put on a high-fat diet, that's the black line. 

They gained a lot of fat. But if they were on high-fat plus antibiotics, they gained even more. That was male mice on the top, and female mice it's similar, but it's worse. 

The female mice on the high-fat diet gained five grams of body fat. High-fat diet plus penicillin, 10 grams.It doubled the amount of body fat. So the antibiotic potentiated the effect of the high-fat diet. Up to this point, the mice were getting antibiotics for their whole life.




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So next we asked, would the changes persist if the antibiotic exposure was much shorter?

So in addition to lifetime antibiotics, we only gave antibiotics for 8 weeks, or only for 4 weeks. Here's the effects on total mass, muscle mass, fat mass. All the antibiotic regiments had the same effect. So even 4 weeks was enough. That was enough for the full effect.



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So then we were interested to see what's the effect of the antibiotic on the microbiome. So this slide is a little complicated. I'm going to tell you about it very slowly.

First, we're going to look at what is the composition of the microbiome in the mice that are 3 weeks old. And at 3 weeks, really there are only two groups of mice. The mice that received antibiotics shown in orange, and the mice that didn't receive, the control, shown in black. On the left side is what we call a principal coordinates analysis. Each dot is the composite of the microbiome in one mouse. 

And what we can see is that the black dots and the orange dots are similar in their distribution, but they're not identical.That's not surprising. One group is getting antibiotics, the other is not.




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Now we're going to look at 8 weeks. And at 8 weeks, we actually have three groups of mice.

Control mice, no antibiotics.Continued antibiotics,But we have another group in blue that got antibiotics for 4 weeks and then stopped. So now, when we look at the dots on the graph, we see, between the controls in black and the antibiotics in orange, there's more distance. That's not surprising.

One group is getting antibiotics. But the group that got antibiotics then stopped, their microbiota have become normal. But the effect on the body fat is permanent. So this was our most important evidence that if we change the microbiota early in life, even if it's short, it will have permanent effects. 




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And we think that's what's happening in people as well.To understand this further, we did a transplant of microbes in mice that received antibiotics or did not. We harvested their microbes from their intestine, and we gave them to germ-free mice.

And now we're establishing their new populations. These are mice that had no bacteria at all.

And we followed these mice for the next 5 weeks.They did not receive any antibiotics. And at the bottom, we can see the effects. The black line is the control group. The antibiotic perturbed microbiota increased the total mass of the mice. It didn't affect their muscle mass, but it affected their fat mass. So the signal was in the microbiota, the altered microbiota is carrying the metabolic signal.




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Now, we've been interested in other diseases. Another student in the lab, Alexandra Livanos, was interested in type-1 diabetes. 

Her idea was that early-life antibiotics would change the gut microbiome and lead to type-1 diabetes in a special kind of mouse that gets this spontaneously. 

She hypothesized it would be due to changes in the expression of genes in the intestine, and to populations of t-cells in the intestine. 

She's shown every part of this.She graduated and got her degree.

现在,我们对其他疾病产生了兴趣。实验室里的另一个学生,Alexandra Livanos,她对1型糖尿病感兴趣。




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So let me begin to finish up by saying, our ideas that antibiotics are having an impact on long-term health by how they affect the microbiota. 

Our idea is that, in health, the ancient gut microbes are talking to our stem cells, they're guiding them. Those conversations are telling them how much fat to develop, how much muscle, how much bone, what should their immune cells be like.

That early development leads to long-term development. But in antibiotic-treated individuals, or individuals who have missing microbes, the gut microbiota is different. The conversations are different. 

The early-life development is different, and the long-term physiology is different. This is our major theory.





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So what's the future going to bring?

Here, we go back to this idea of the step going down, each generation getting worse. 

The blue line might be a country like the United States. The red line might be China. It started to develop later, but it's developing so rapidly. Maybe the yellow line is a country in Africa or Latin America that's just beginning to develop. So we're all going down.

What will the future bring?Will it continue to go down? Will we stop it from going down any further? Or will we begin to restore?

I think that we will have to begin to restore, otherwise we will have many of these modern plagues.






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So I think that the doctors of the future, when they examine a baby, are going to examine the baby's diaper. 

And they're going to ask, does this baby have all the microbes that they should have? The global microbes that every baby should have? Or certain personal microbes that that particular baby should have based on who that baby is and what's their genetics? 



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And if the baby doesn't have those microbes, I'm thinking the next generation of doctors are going to give those microbes back to the baby to try to restore their health, and to study what's going to be the effect on the baby.


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Is this going to make them better or not?

This is what I think the medicine of the future is going to look like.



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So what's my advice for mothers in China, mothers everywhere in the world?

We need to reduce antibiotic exposures unless they are medically necessary, unless the doctor says this child, this person must have an antibiotic. 

  • We need to avoid antibiotic taking of young girls and young women unless necessary. 

  • Avoid taking antibiotics in pregnancy unless necessary. 

  • Don't have a cesarean section unless it has to be done. 

  • Don't give your baby antibiotics unless it has to be done. 

  • Babies should be nursed as long as possible. 

  • We should avoid foods that have antibiotics in them. 

  • We should avoid drinking water that contains antibiotics.

This is a lot to think about, but I'm very happy for everyone's attention.

Thank you very much.


  • 我们要减少接触抗生素,除非这是医疗所必须,除非医生说这个孩子,这个人必须使用抗生素。

  • 我们要避免年轻女孩和妇女使用抗生素,除非必要。

  • 避免孕期服用抗生素,除非必要。

  • 不要剖腹产,除非必要。

  • 不要给你的宝宝使用抗生素,除非必要。

  • 婴儿应接受尽可能长的母乳喂养。

  • 我们应该避免食用含有抗生素的食物。

  • 我们应该避免饮用含有抗生素的水。