There is a "seesaw" composed of 284 strains of intestinal bacteria in the intestinal flora of the human body, which is divided into two teams, one is the "cornerstone functional group" and the other is the "pathogenic functional group", which are interdependent and restrictive. When the "cornerstone functional group" is dominant, the human intestinal flora is in a healthy state; When the "diseased functional groups" are dominant and the advantages are increasing, it not only indicates that there is a problem in human health, but also these "diseased functional groups" are also important participants in the disease state.
The research project led by the "Joint Laboratory of Microbiome and Human Health" of Shanghai Jiao Tong University and Rutgers University in United States has identified the core members of the human gut microbiota for the first time, which will bring a disruptive breakthrough in disease treatment and health management. On the evening of October 7, the results were published online in the top international academic journal "Cell" with the title of "A Core Microbiota Characteristic that Can Be Used as an Indicative of Health".
Zhao Guoping, an academician of the Chinese Academy of Sciences, commented on this achievement, saying that this study successfully transformed the originally difficult to quantify microecosystem into a network structure that can be quantitatively analyzed, and completed the transition from the identification and analysis of "strain metabolism" based on traditional taxonomy to the dynamic analysis of the function of "core flora" based on ecology, which is not only a major breakthrough in microecology theory, but also a major innovation in microbiome research methods.
The "core flora", which is difficult to find the real body, has finally been found
The gut microbiota not only affects a person's digestive system but also plays a key role in maintaining a person's overall health. Patients with a variety of chronic diseases, including obesity, diabetes, cardiovascular and cerebrovascular diseases, Alzheimer's disease, chronic kidney disease, liver disease and cancer, are often accompanied by dysbiosis.
Clinical studies and practices have shown that transplanting the intestinal microbiota of healthy people to patients can alleviate the symptoms of a variety of diseases. This means that in the gut microbiota of a healthy donor, there are key functional bacteria that are necessary to maintain human health. Academics refer to all these bacteria collectively as the "core flora". The famous microbiologist Martin · Blazer proposed the "disappearing microbe" theory, which believes that the reduction or loss of core bacteria will lead to dysbiosis, which may be an important reason for the modern epidemic of many chronic diseases.
But what exactly are the members of the core microbiota? There has been no consensus in the scientific community. In particular, there are differences in genetics, diet, and living environment of each person, which makes it difficult to find core microbiota members using existing microbiota research methods, and also seriously restricts the research and development, supervision and application of disease prevention and treatment technologies targeting intestinal microbiota.
"The reason why we were able to make a breakthrough in the identification of core microbiota members this time is mainly due to the breakthrough of research ideas and the innovation of research methods." Professor Zhao Liping, the head of the study, the director of the joint laboratory and a tenured professor at Rutgers University in United States, told reporters that the research team innovatively borrowed the concept of "functional groups" in macroecology, and believed that different types of bacteria do not play a role alone, but "huddle together for warmth" in a group collaboration. At the same time, the team conducted a network analysis of the bacteria's genome to divide the gut bacteria into different "functional groups".
Based on the new high-resolution microbiota sequencing big data analysis technology developed by the team, by tracing the bacterial genome sequence, the scientists discovered the ecological behavior of unknown bacteria and their impact on human health that could not be analyzed in the past.
Two competing bacterial "functional groups" that affect human health
In order to find the members of the core microbiota, the research team used nutritional intervention as an environmental perturbation and focused on the bacterial functional groups that can maintain a stable cooperative or competitive relationship after environmental perturbation.
The research team conducted a three-month randomized controlled trial on 110 patients with type 2 diabetes. The clinical results showed that through the intervention of a high-dietary fiber diet, more than sixty percent of the patients in the experimental group had glycosylated hemoglobin reduced to less than 7%. However, one year after the end of the trial, the patient's glycosylated hemoglobin level rebounded back to baseline levels. The overall structure of the gut microbiota also moved away from the baseline after the intervention, and finally returned to the pre-intervention state, experiencing a "roller coaster" of drastic changes.
The team conducted microbiota network analysis on stool samples at three time points before intervention, after intervention, and one year after follow-up, and screened out 141 strains of bacteria that could stably maintain cooperative or competitive relationships at different time points. It was found that these bacteria constituted "two competing functional groups".
Within the two functional groups, the bacteria are like "iron buddies" and maintain a stable cooperative relationship; The two functional groups maintain a stable competitive relationship, similar to "sworn enemies". These two functional groups affect human health through the network structure model of "seesaw", in the way of "you rise and I fall".
The team also found that this "seesaw" model is not only a characteristic of the microbiota unique to diabetic patients, but also a characteristic of the core microbiota of the human body. At the same time, these 141 strains of bacteria, although they account for only about 8% of the bacteria in the entire intestinal ecological network, are the "social maniacs" of the bacterial world - they have ecological relationships with more than 85% of other bacteria. If this part of the bacteria is removed, the entire ecological network will completely collapse, and the remaining bacteria will be almost isolated.
Combining data from patients with seven diseases from five countries, the team further found that the "seesaw" structure of two competing functional groups was also maintained in gut samples from patients with diabetes, cardiovascular disease, ankylosing spondylitis, colorectal cancer, inflammatory bowel disease, cirrhosis, and schizophrenia, as well as healthy controls.
With the help of the "seesaw" model, or start a new chapter in personalized medicine
Scientists further hypothesize that if people of different geographies, races, and disease species had their own "seesaw" core flora, then
Is it possible to construct a universal "seesaw" model that is common to all of humanity as the core microbiota of the human population?
To test this hypothesis, the research team selected 284 strains of bacteria that contributed the most to modeling, and finally formed a general "seesaw" model consisting of two steadily competing functional groups.
"After our repeated validation, the results have been consistent: the 'seesaw' model is indeed ubiquitous in patients with different diseases and their healthy controls, and is an important core microbiota feature." Zhao Liping said that the discovery of the "seesaw" model of the core microbiota is like clinical trial data from different laboratories suddenly learning the same language and can communicate with each other, which is tantamount to realizing the "same track, the same book, and the same line" in the field of microbiota research.
So, what is the value of the "seesaw" model of the core microbiota for personalized medicine?
Take immunotherapy, for example. Current immunotherapy clinical trials can only evaluate the average response of the population, and cannot predict the specific response of the individual, resulting in many patients blindly receiving treatment and missing the best time for treatment. The research team integrated microbiota data from 11 immunotherapy clinical trials in advanced melanoma, B-cell lymphoma, inflammatory bowel disease, and rheumatoid arthritis into a "clinical treatment dataset" to predict patients' personalized responses to immunotherapy using a universal "seesaw" model. It was found that the universal model can help doctors predict the patient's response to different therapies before treatment, so as to optimize the treatment plan and improve the accuracy and efficacy.
"Pathogenic functional groups" are not "germ functional groups" or "harmful functional groups"
The research team also analyzed the functional genes carried by these two competing functional groups.
The results showed that the beneficial functional groups associated with disease remission were mainly composed of short-chain fatty acid-producing bacteria, which were able to degrade dietary fiber and produce short-chain fatty acids. Short-chain fatty acids play a vital role in many life processes such as nutrient supply, immune regulation, and mental health. Moreover, these bacteria carry almost no antimicrobial resistance genes or virulence factor genes that can cause disease, so they are safe for humans.
Another functional group associated with disease progression is composed mainly of opportunistic pathogens, which carry almost all known types of resistance genes and virulence factor genes. Numerous studies have shown that opportunistic pathogens can train the immune system of newborns and keep the immune system of adults moderately alert when controlled in numbers. However, if these bacteria overgrow, they can trigger systemic inflammation, which in turn promotes the development and progression of a variety of diseases.
The research team named the functional group dominated by short-chain fatty acid-producing bacteria as the "cornerstone functional group" because these bacteria inhibit the overgrowth of opportunistic pathogens by producing short-chain fatty acids to acidify the intestinal environment, and their function is similar to the stabilizing effect of trees as "cornerstone species" on forest ecosystems.
The functional groups composed of opportunistic pathogens are named "pathogenic functional groups", but they are also not "pathogen functional groups" or "harmful functional groups". Because these bacteria are not typical pathogens. At low levels, they are essential for maintaining the normal functioning of the body's immune system and are members of the human core flora; It is only when its number gets out of control that it is harmful to the human body.
Zhao Liping likened the cornerstone functional group bacteria to "big tree fungus". He said that only when the "tree fungus" is dominant, the microecosystem of the gut can remain stable like a dense forest, inhibiting the overgrowth of bacteria and other pathogens in the pathogenic functional group, thereby maintaining overall health. This discovery provides a new target for disease prevention and treatment.
Zhao Liping said that the discovery of the seesaw characteristics of the intestinal core microflora, especially the importance of "big tree fungus" to health, has opened up a new way for personalized medicine and precision nutrition. "Next, we need to develop a series of tests and treatment options that can be used in clinical practice and prove their efficacy in different diseases."
The study was co-authored by Prof. Liping Zhao from Shanghai Jiao Tong University and Rutgers University in United States, Prof. Yongde Peng from Shanghai First People's Hospital affiliated to Shanghai Jiao Tong University, Prof. Chenhong Zhang from Shanghai Jiao Tong University, and Chief Physician Yu Shi from Qidong People's Hospital. Research Assistant Professor Wu Guojun of Rutgers University in United States, PhD student Xu Ting of Shanghai Jiao Tong University, Research Assistant Professor Naisi Zhao of Tufts University in United States, Assistant Professor Yan Y. Lam of the University of Hong Kong, and Chief Physician Ding Xiaoying of Shanghai First People's Hospital affiliated to Shanghai Jiao Tong University are the co-first authors.