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At present, about 2 billion people in the world are obese, and obesity is also a high risk factor for causing diseases. Amazingly, obesity and intestinal flora are also closely related. In the SELF Forum Women’s Workshop, Zhang Chenhong, an associate researcher at the School of Life Science and Technology at Shanghai Jiaotong University, not only explained the factors related to obesity, but also shared the wisdom of using meals to maintain healthy flora.

Zhang Chenhong

Associate Professor, School of Life Science and Technology, Shanghai Jiaotong University

The following content is Zhang Chenhong’s speech record:

Hello everyone! I am Zhang Chenhong from Shanghai Jiaotong University. In this topic that I want to talk about with you the buddies which living with us all the time, but we never saw.

The photo on the left is Michelangelo’s David statue. Everyone is familiar with it. He is considered the perfect human body. But what would it look like if we made a David statue according to the average figure of the global people today? It will be the photo on the right – a fat David.

Why do you say that? Because obesity is now a very serious global problem, there are probably 2 billion people in the world who are all obese. For example, we can see from the map that in the United States in 1985, the proportion of obese people was still very small. By 2014, almost all of the maps of the United States had become red, and the obesity population had greatly increased.

In developing countries such as China and India, the problem of obesity is equally serious. China is the country with the largest obese population in the world, and even more serious is the obesity problem among adolescents and children. Obesity during adolescence will lead to many related issues after adulthood.

In fact, obesity is not just a beautiful problem. Obesity-related diseases are many, and obesity is a high risk factor for many diseases, such as type 2 diabetes, cardiovascular disease, and many types of cancer.

Take type 2 diabetes, for example, it is not just a matter of early high blood sugar, medication control problems, there will be many serious complications later, such as diabetic nephropathy, diabetic eye disease, diabetic vascular disease, diabetes heart disease, etc. And so on, most diabetic patients eventually died of serious complications.

For Chinese society, the problem of diabetes is also very serious. According to the epidemiological survey conducted by the team of Ruijin Hospital of Shanghai Jiaotong University, 11.6% of the population in China has type 2 diabetes and 50% of the population is pre-diabetic.

Everyone can think of how many people in China, if these 50% of the people all develop diabetes? This will be a huge social and medical burden, and our medical system will not be able to afford it. Ultimately, it will only lead to the collapse of the entire medical system. Therefore, obesity and related diseases can be said to be a research hotspot in the current medical field.

What are the causes of obesity? Of course, genetics is a non-negligible factor. After years of research, scientists have found a lot of genetic sites related to obesity, but the contribution of these genetic sites to the ultimate occurrence of obesity is actually not large. And we imagine that mutations take some time. How could it happen that in a short span of 20 to 30 years, the world’s population pool of genes suddenly changed dramatically, and everyone suddenly became fat? So from a genetic point of view it cannot explain the rapid prevalence of obesity.

So what is the reason? Reasons that everyone may recognize, such as changes in lifestyle and dietary structure, have changed from eating cereals to eating more protein and fat. There are no other factors between the diet structure, lifestyle, obesity, and obesity-related diseases.

Scientists have set their sights on the symbiotic microbiome of our partner who lives with us. The earth is actually a world of microorganisms. Microorganisms are found in all the ecological environments of the earth. In our open systems such as the skin, mouth, genital tract, and intestine, microbes survive. Even in places that were previously thought to be free of microorganisms, such as the lens of the eye, microbes are now found to be present.

How many microorganisms are there with us? Take the example of the intestine. There are 1 to 2 kilograms of microorganisms in the intestine. 95% of the body’s symbiotic microorganisms are found in the intestine. Its cell number is 10 times that of human mammals. That is, only 10% of humans are mammals, and the other 90% are actually microbes, so humans are a super organism.

The number of these microorganisms is so great. So what’s their function? We know that there are more than 30,000 genes encoded by humans, and the number of genes encoded by these microorganisms that are symbiotic with us is 100 to 150 times the number of genes we encode, so they have very rich metabolic potential to regulate humans. Nutrition, immunity, metabolism, etc.

From the microbiological point of view, we are their fermenters. The nutrients we eat, which cannot be digested and that are not digested, will enter our intestines as nutrients in the gut to help them grow. There are also some epithelial cells that we have shed and so on, all of which can be used as their nutrients. We cultivated these bacteria in the intestines, and they were discharged through defecation. Therefore, human beings are in fact a flow incubator capable of speaking and walking.

So what did these microbes do during the growth process? They produce a lot of metabolites. For example, when using dietary fiber and carbohydrates for fermentation, they produce substances like short-chain fatty acids. Such substances have a beneficial effect on people, such as anti-inflammation and increasing satiety.

In addition, microorganisms also produce in vivo needs that some people cannot synthesize themselves, such as vitamin D, vitamin K, and other very important substances. At the same time, some metabolites of microorganisms may be harmful to the human body. For example, when a substance such as fermented protein is fermented, the product of the microorganism is a class of toxic and harmful substances such as benzene rings and aromatic compounds.

Fecal odor, in fact, comes from inside maggots. These poisonous and harmful substances may cause genotoxicity, which may lead to mutations in our genes; may cause cytotoxicity, and may cause cancer and the like. There are also neurotoxins, which means that it may affect our nervous system. For example, it may have a close relationship with autism and depression.

Our previous understanding of human health is that our health is determined by the influence of our human genome on the external environment. But now it seems that our own genome and the symbiosis with our symbiotic microbiome should jointly deal with the regulation of the external environment to determine our health and disease. Since the microbiology group that is symbiotic with us is so important, when did we begin to realize its role? Is it just recent? Actually not.

The winner of the Nobel Prize in 1908 was a Russian. He was called Mechnikov. He once had a hypothesis that he was a specific substance produced by certain members of the intestinal flora – toxic and harmful substances. Entering our body is a source of aging. In Chinese medicine, there is also a saying that “dung poison enters the blood and all diseases begin to swell” and refers to the harmful effects of the harmful metabolites of the intestinal flora on people.

But these are all hypotheses, and even philosophy, there is no evidence of scientific experimentation, and it has not been confirmed. Why is this so? Because the intestinal microflora lives in our intestines, it’s actually a black box. We can’t open it up for a look. And it is a very complex community. There are so many species and cells in it that interact with people. So when our technical means couldn’t reach it, we started by using culture to understand our intestinal flora. This is far from enough, because more than 90% of the bacteria in the intestine cannot be cultured.

So we don’t know what’s inside and what their function is. With the development of science, scientists began to use molecular biology methods to study the intestinal microflora, such as fingerprinting, but there is still no way to make the resolution high enough, and can help us to clearly recognize their abundance and Functional composition.

Until the beginning of this century, sequencing technology has been greatly developed, especially the emergence of second-generation sequencing technology. It allows us to greatly increase the sequencing throughput. We started to use sequencing to study the intestinal flora. Instead of using culture methods, we put the total DNA of the intestinal microflora out and then perform high-throughput sequencing. We can know what bacteria are inside, what the abundance of each bacteria is, and what they are. What kind of functional gene is there?

Recently, we have applied various techniques of group science, including the study of its metabolites, protein genomics, and other multiomic techniques, to the study of bacterial flora. Through the integration of multi-omics big data, to help us understand the function of this flora.

For the study of the association between bacterial flora and disease, the earliest studies began with obesity. American scientist Jeffery Gordon has published articles on the relationship between flora and obesity since 2004. He found that the function and structure of the intestinal flora of fat people and lean people are different, and he transplanted the fat and thin people’s flora to fecal animals through fecal transplantation.

The so-called sterile animals are kept in a special isolator. The whole environment is sterile. It is sterile under both the body and the body, so we can transplant human germs into sterile mice. In mice transplanted with a fat population, fat accumulation increased; mice that were transplanted with a lean population did not.

It seems that the gut microbiota seems to be a whole, it is not only a concomitant change, it may be a pathogenic factor.

European scientist Patrice Cani et al. found that Gram-negative bacteria in the intestinal microflora, whose cell wall component is called lipopolysaccharide, can cause immune reactions, also known as endotoxins. After it enters the circulatory system it causes chronic inflammation, while chronic low-level systemic inflammation eventually leads to fat accumulation.

So is the microbiota only as a whole, or is it that there are many key members who play a more important role in it? In our previous work, we found a person who was obese. He had an extremely high abundance of bacteria at 180 kilograms. After weight loss, the bacteria could hardly be found.

So we separated it and transplanted it into the body of a sterile mouse. As a result, the mice became fat. Like a mouse transplanted with a whole group of obese people, transplanting only one of the bacteria, the mouse became fat. In the intestine, we can also find bacteria that cause obesity, such as the infectious disease.

Since the intestinal flora is so important in the development of obesity and related metabolic diseases, is it possible to improve and treat metabolic diseases by regulating the flora? We know that after we are born, if we want to solve the disease through the regulation of genes, of course, there are many scientific and technological developments, such as CRISPR technology, but there are still problems in safety and ethics.

However, regulating the flora may be relatively easy and can be done. How do we do it? It is its nutrition that determines the flora, which is our diet. Therefore, we can change the structure of our diet to change the flora, to intervene and adjust health, as well as obesity and diabetes.

What kind of diet is reasonable? What kind of diet can maintain healthy bacteria? After so many years of research and knowledge, we first discovered that the beneficial bacteria in the intestinal microflora used more dietary fiber, and the use of dietary fiber products was also beneficial. So we have done such a product that meets dietary nutrition. The materials we use include glutinous rice, wolfberry, etc. They are rich in dietary fiber and have a lot of complex dietary fiber inside. In addition, some plant extracts and prebiotics were added.

Prebiotics are familiar to everyone, like oligofructose and inulin. Our diet contains very complex, high-content dietary fiber, and we also need to satisfy people’s needs for nutrients such as carbohydrates, protein, and fat. Therefore, we call this meal the Feed me Feed my bacteria, which is a set of meals that both feeds people and raises bacteria.

So what’s the effect? It helps the growth of beneficial bacteria in the intestinal tract and reduces the abundance of harmful bacteria in the intestinal tract. This is an example of an obese adult patient. When we met him, he was 174.9 kg. After 23 weeks of intervention in our diet, he lost 50 kg in weight and became the figure on the right.

This is just an example. We use it for larger clinical studies. We organized 123 obese patients and then intervened through this diet. After the intervention, their intestinal flora has undergone very large changes, and they have lost their weight, and their sugar metabolism and lipid metabolism have improved significantly.

Can this diet be used for obesity caused by genetic factors? Is it possible to compensate or improve the innate influence by adjusting the flora? The example we are looking for is called Prader-Willi syndrome, which is the chubby Willy syndrome, caused by the loss of a large fragment of the parent’s chromosome 15. These children will have insufficient muscle tension at the time of birth, so they will not have the strength to even eat milk, resulting in malnutrition.

But once weaned, they will have a constant sense of hunger. Eating behavior is very unusual, and we must keep eating. If you don’t give something to eat, they will even go to the trash to find food, and they will also grab something from other children. Therefore, they will develop into extremely severe and severe obese patients when they are very young. Then there will be very serious diseases, such as type 2 diabetes and cardiovascular diseases, so their life expectancy will not be very long.

For obese patients caused by such genetic problems, only strict weight control can improve the quality of life and extend life expectancy. However, there is no particularly good clinical method to solve this type of hereditary obesity. So, is there any use for the adjustment of intestinal flora?

This example is a 14-year-old child with Prader-Willi. When he arrived at the hospital, he was only 14 years old and weighed 140 kg. Then we went through genetic tests and found that he was indeed a child with Prader-Willi, so we had dietary intervention on him. Conduct more than 200 days of intervention and use only our diet to intervene during the intervention. He was not allowed to exercise and he had no other medical treatment. When he was discharged, he lost weight to 83 kilograms. He went back home and continued to eat our diet. Using this method, the final weight was reduced to about 70 kg and it remained for a long time. It has remained relatively stable for more than four years.

This example means that this genetic problem seems to be improved by adjusting the flora. Is this not the case? We also organized more than twenty children with Prader-Willi to conduct clinical research and found that the use of this diet actually changed the structure and function of the intestinal microbiota. It was discovered through the detection of urine metabolites. The whole metabolites associated with the flora have also changed. The beneficial metabolites increase and the harmful metabolites decrease.

In other words, by changing the flora, although the dysbacteriosis of the intestinal flora is not the initial driving factor in hereditary diseases, it is also very important. We do not interfere with it, and it is also a function that can improve people’s health.

What about obesity-related diseases? For example, in type 2 diabetes, we have clinical interventions in patients with a history of 5 to 10 years and Type 2 diabetes with excessive HbA1c. Of course, our diet will change slightly to meet the needs of people with type 2 diabetes of different ages. .

After eating this high dietary fiber diet, through metagenomic sequencing and other methods, we found that a special type of bacteria capable of producing short-chain fatty acids in the intestine increased, and after such bacteria were increased, short-chain fatty acids increased and short-chain increased. Fatty acids will regulate intestinal peptides, such as the secretion of GLP-1. The increase of GLP-1 will increase the secretion of insulin, which will be beneficial for blood sugar control.

Not only that, this type of beneficial bacteria will change the environment of the entire gut because of acid production. And the advantages of various niches such as substrate competition will reduce the abundance of harmful bacteria. For example, harmful metabolites such as hydrazine and hydrogen sulfide have also been greatly reduced. Hydrazine and hydrogen sulfide have the function of inhibiting GLP-1 secretion. Short-chain fatty acids increase, hydrogen sulfide and hydrazine decrease, and eventually the total secretion of GLP-1 increases, thereby improving the host’s glycometabolism.

Our study of this part of diabetes has recently been published in the journal Science. It has also aroused everyone’s concern. Eating more dietary fiber, changing the intestinal microflora, and possibly controlling the disease can still be used clinically.

There are other ways to change the intestinal flora. In addition to changing the dietary structure, the ancient Chinese people were still very wise. “Seven-point fullness can live long”, which is very correct. After modern scientific research, dieting – diets that do not cause malnutrition – from single-celled yeast to mice, rabbits, dogs, to monkeys that are most like humans, do whole-life dieting trials. It is able to delay aging and prolong life.

Of course, there is no whole life cycle dieting study in humans, and short-term dieting does reduce weight and improve metabolism. A recent study also reported that dieting can indeed change many of the factors associated with aging.

Is dieting related to intestinal flora? We found that the gut microflora of the animal during the whole life cycle diet has a very special structure. The ratio of a kind of beneficial bacteria called Lactobacillus is particularly high. Does this have any contribution to health?

We have isolated this most abundant lactobacillus and it is a Lactobacillus. After it was isolated, we found it was indeed anti-inflammatory in in vitro cell assays. We use animal models that have a short life cycle, nematodes, and their food is bacteria.

In the lab, we usually give it E. coli, but now it has been extended to life after it has been replaced with Lactobacillus. If this strain is fed to elderly mice, the systemic low level of inflammation in the mice is reduced, and the intestinal barrier function is improved. These aging-related factors are improved.

In mice, this is the case. We have no bacteria that may have similar functions found in the human body. Maybe we find out that it is finally taken out. It may help everyone to fight against aging and prolong life.

After these studies, we found that dysregulated intestinal flora can cause many related diseases. We regulate them through diet, drugs, or probiotics, restoring their structure to a more reasonable intestinal flora structure. This has greatly improved the health of the host.

The reason that the intestinal microflora exists, I have always believed that it is definitely not a bad thing. It has survived and co-evolved with the human body for so many years. If it is to make us sick, it is so smart in human evolution. It was thrown in the middle of the morning.

Its role must be to support and maintain our health and provide us with essential substances for many people. So what can we do to maintain a healthy intestinal flora? Let them support our health instead of giving us trouble.

As a scientific researcher, of course, it continues to discover the mechanism: what is its pathogenic mechanism, or what is its mechanism for improving our health, and what is the substance? But for everyone, a relatively simple approach is to maintain a healthy diet and maintain a slim body, hoping that everyone can live healthy and longevity.

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