What causes schizophrenia? This is one of the most challenging scientific questions published on the 125th anniversary of the journal Science. About half of the patients do not respond to current antipsychotic drug treatment, therefore, understanding the mechanism of schizophrenia and finding more effective treatment methods has become the consensus of psychiatric researchers around the world.
Working with scientists around the world
< p>Reporter:
Professor Zhu Feng, you and your team have decided to join the International Psychiatric Genomics Consortium (PGC) and participate in this What is the purpose of this study?
Zhu Feng: cancer, neurodegenerative disease, mental illness The pathogenesis of human complex diseases is long and the mechanism is complex. In the past 20 years, an important experience of the academic community in exploring such diseases is that the whole world joins hands to form a “big army” to realize the “war of annihilation”. Starting from the Human Genome Project, a country, a region, or even the whole world has been concentrated, and more and more similar research programs have been launched, such as the “Cancer Moon Shot Program” in the United States and the “Joint Research Program on Neurodegenerative Diseases” in the European Union. The PGC we joined is a global research consortium that unites global psychiatric experts to focus on key issues.
In recent years, with the rapid development of high-throughput detection technologies, such as sequencing and mass spectrometry, our research on disease mechanisms has changed from traditional The blind-to-image research method of single molecules and pathways has developed into an integrated and systematic research paradigm based on multi-omics analysis, which is also the basis for the realization of precision medicine in the field of mental diseases in the future. To put it simply, now we use one medicine for thousands of people, and in the future, it will progress to ten medicines for thousands of people, hundreds of medicines, or even one medicine for one person, that is, individualized medicine.
A complex disease like schizophrenia has a high degree of heterogeneity in etiology and pathological mechanisms despite similar clinical manifestations. of. There are both similar onset links and individualized onset links among different individuals. To systematically and comprehensively understand the commonalities and individual problems of diseases, large-scale studies are needed, and a global patient sampling can be used to fully describe the molecular and cellular panorama of disease occurrence. This is the original intention of our participation in PGC. It turns out that when global samples were pooled together, many disease risk genes that were previously undetectable in a single population were identified.
Untangling the relationship between the gut-brain axis and mental illness
< span>Reporter:
You were primarily engaged in the genetics of schizophrenia, and now you have moved on to schizophrenia and gut microbiota research, why this change?
Zhu Feng: Joining an international research team to study together allows us to keep up with world-class research trend. But at the same time, we also need to develop and advance our own unique research directions. Therefore, after graduating with a doctorate in 2013, I spent more than two years sorting out the research directions of schizophrenia at home and abroad at that time. I found that there are various research directions for schizophrenia, from epigenetics, brain function imaging, single-cell sequencing, to brain organoids differentiated from stem cells, and they all seem promising.
At that time, the gut-brain axis was still a very new concept, and many colleagues disagreed with the evidence that gut flora affects the brain. At the same time, the sample size of PGC’s genome research on schizophrenia has reached tens of thousands, but the genetic loci found can only explain 30% of the disease risk. In this regard, we speculate that the role of the gut microbiota genome, which is the second genome of the human body, in the pathogenesis of schizophrenia has not been valued. In addition to sorting out research papers on schizophrenia in 6 journals, including Nature, Science, Cell, New England Journal of Medicine, Lancet, and American Medical Journal, I repeatedly discussed with Professor Ma Xiancang, Ultimately, we take the association of gut microbiota, gut-brain axis and schizophrenia as the main direction of the team’s research.
After determining the research direction, the team launched the world’s first metagenomic study of gut microbiota in patients with schizophrenia. After 3 years of research, the team mapped the strain-level metagenomic map of the disease for the first time, and found more than 20 schizophrenia-risk gut bacteria and many human gut-originated strains with neuromodulatory effects. The results were published in Nature Communications and Molecular Psychiatry, respectively.
Development of living biological drugs for mental illness
Reporter:
The relationship between intestinal flora and schizophrenia has been clarified. What impact will it have on clinical practice in the future?
Zhu Feng:2017, when seeing from schizophrenia After data showed that a strain isolated from the guts of patients with psychiatric disorders was able to induce marked behavioral disturbances in mice, we realized that there was promise in the treatment of mental illness by interfering with the gut microbiota. The immune system is an important way for the intestinal flora to regulate the bodynoodle. Considering the existence of systemic immune disorders in schizophrenia patients, our team focused on the causal relationship between intestinal flora disturbances and immune abnormalities in schizophrenia patients.
In November 2021, the team’s research results on the mechanism of the gut-immunity-brain axis in schizophrenia were published in a well-known international journal in the field of mental illness in the journal Molecular Psychiatry. This study delineates the molecular and cellular basis of impaired immune function in patients with schizophrenia and proposes that innate immune deficiency and impaired gut barrier lead to bacterial translocation in the gut, which in turn promotes blunting of the innate immune response. These findings provide a new explanation for the pathological mechanism of immune and brain abnormalities in patients with schizophrenia, and provide multiple potential targets for the development of live bacteria drugs for the treatment of schizophrenia from the gut.
Since the intestinal flora can affect the occurrence and development of mental diseases, it is feasible to find good medicines from the treasure house of human symbiotic bacteria. At present, our team has built the world’s leading biobank (feces, serum, peripheral blood mononuclear cells) and databases (fMRI data, metagenomic data, whole-genome typing data, single cell Transcriptome data, immune cell transcriptome data and clinical phenotype data), with a total of more than 200,000 samples and data. Using machine learning methods, the team established a predictive method for psychiatric disorders and related phenotypes based on gut microbiota and serum metabolites, with greater than 99.4% diagnostic accuracy for schizophrenia and depression.
More importantly, relying on this biological sample library, we have established a human symbiotic bacteria strain library, and more than 7,000 strains have been stored in the library. , which includes multiple strains with significant improvements in anxiety, depression, systemic inflammation, and neuroinflammation. These are important support for our future development of living biological drugs. Living biopharmaceuticals are oral live bacteria with therapeutic effect, containing a single strain or a combination of multiple strains. In the basic research of flora, we keep pace with foreign counterparts, but in the research and development of living biological drugs, we are several years behind. Therefore, the development of a new generation of living biological drugs for mental illness is the goal of our team in the next stage.
Author: HealthHealth Reporter Zheng YingfanPlanning: Fang TongEditor: Wang Jianying Review:Fang Tong
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