A personalized map of drug metabolism by the human gut microbiome. A review by Cell Press.

As the world's leading academic publishing house in the whole science field, cell press cooperates with the "Youth Innovation Promotion Association of Chinese Academy of Sciences" to set up the column "review of youth Promotion Association" in order to enhance academic interaction and promote international exchange.the 10th issue of the column was published by Wang Zuoyun, associate researcher of the center for excellence in molecular and Cell Sciences, Chinese Academy of Sciences (Shanghai Institute of Biochemistry and Cell Biology) and member of the youth innovation promotion association of Chinese Academy of Sciences.long press the picture and scan the QR code to read the paper. Intestinal microbiota is closely related to human life, such as the impact on health, disease and development, and the response to drugs and treatment.when it comes to drug therapy, oral administration is the most common way of administration nowadays. In this process, drugs will coexist with microbial communities in the small intestine and large intestine for a long time. Therefore, it is particularly important to study the role of intestinal microflora in drug metabolism (falony et al., 2016; Li and Jia, 2013).previous studies have shown that the diversity and richness of microorganisms also vary greatly among healthy individuals, which is one of the reasons why individuals have great differences in drug response (human microbiology project, 2012).there is increasing evidence that intestinal microbiome plays an important role in this difference, but its molecular mechanism remains largely unknown.in June 2019, the research team led by L. Goodman published "mapping human microbiology drug metabolism by gut bacterium and their" in nature, a top international journal In this study, high-throughput genetics and mass spectrometry were used to identify the gene products of drug metabolizing microorganisms, and the drug metabolism map of human microbiome was drawn by intestinal bacteria and their genes (Zimmermann et al., 2019).previous studies have shown that the interaction between intestinal microflora and multicellular hosts is multifaceted: the metabolites produced by the microbial flora will affect the host's life activities; the flora itself also functions as a part of the host's intestinal barrier; the metabolites produced by the host affect the growth and reproduction of the flora; there are also interactions between the microbial flora and the host Direct interaction (Visconti et al., 2019).in the past, a lot of studies on intestinal microorganisms were carried out by isolating single colonies, but the metabolic effect of microbial flora on drugs was often ignored.in order to solve the above problems, Mohamed s Donia's research team first screened an efficient medium to maximize the diversity of the original flora of the sample. Then, 575 oral drugs were screened using this medium, and 57 drugs that could produce new metabolites or could be completely metabolized by the flora were identified (Figure 1).Figure 1 The screening of high-efficiency medium and the construction of screening system for drug metabolism in vitro were carried out. Then, the experimental samples were expanded and a new medium was re identified, which could maintain the specificity of each sample flora on the basis of considering the biomass and species diversity. Through the screening of drug metabolites, many unreported drug metabolites were found in the study (Fig. 2).} Fig. 2 Identification of new media and screening of drug metabolites. Capecitabine is a widely used anticancer drug, which is suitable for paclitaxel and chemotherapy regimens including anthracycline antibiotics. It is used to treat ineffective advanced primary or metastatic breast cancer. It produces 5-fluorouracil in human body and causes cell damage (meulendijks et al,2016)。in this study, the author found that capecitabine can be deglycosylated, and identified the homologue of the enzyme catalyzing the deglycosylation reaction by homologous compounds in human body. This phenomenon was also verified in mice. Then, the author also compared the richness of the enzyme in the population, and found that the enzyme was mostly expressed in non western countries It also provides reference for clinical administration of capecitabine (Fig. 3).Figure 3 A new metabolic mode of capecitabine was found by MDM screening system. Then, the enzyme that catalyzes the reduction of hydrocortisone to produce 20 - β - dihydrocortisone (20 - β hsdh) was identified by another method. Hydrocortisone was used to treat diseases caused by adrenal insufficiency, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumat Gout, bronchial asthma, etc.by establishing a macro gene library of the first subject and screening by gradient dilution, it was found that 20 - β hsdh could catalyze the reduction reaction, and it was found that the enzyme was widely expressed in the population, but its expression abundance was heterogeneous (Fig. 4).Figure 4 Summary of the construction of macro gene library and screening and identification of 20 - β hsdh full text, the research team selected a special medium, which can maximize the diversity of the original flora of the sample. Using this culture system, researchers screened many oral drugs, and identified the new metabolites produced in the process, through homology analysis and macro base The enzyme catalyzing the two reactions was identified by group screening, and the new metabolic reaction was confirmed in vivo, which provided some guidance for clinical drug administration, and also clarified the important role of intestinal microbiome in drug metabolism, which is of great significance for drug treatment and drug development of various disease indications (Fig. 5). } Fig. 5 Summary of the full text of this paper (click up and down) 1. Falony, g., joossens, M., Vieira Silva, S., Wang, J., Darzi, Y., Faust, K., kurilshikov, A., bonder, M.J., Valles Colomer, M., Vandeputte, D., et al. (2016). Population level analysis of gut microbiome variation. Science 352, 560-564.2. Human microbiology project, C. (2012). Structure, function and diversity of the healthy human microbiome. Nature 486, 207-214.3.Li, H., and Jia, W. (2013). Cometabolism of microbes and host: implications for drug metabolism and drug-induced toxicity. Clin Pharmacol Ther 94, 574-581.4.Meulendijks, D., van Hasselt, J.G.C., Huitema, A.D.R., van Tinteren, H., Deenen, M.J., Beijnen, J.H., Cats, A., and Schellens, J.H.M. (2016). Renal function, body surface area, and age are associated with risk of early-onset fluoropyrimidine-associated toxicity in patients treated with capecitabine-based anticancer regimens in daily clinical care. Eur J Cancer 54, 120-130.5.Visconti, A., Le Roy, C.I., Rosa, F., Rossi, N., Martin, T.C., Mohney, R.P., Li, W., de Rinaldis, E., Bell, J.T., Venter, J.C., et al. (2019). Interplay between the human gut microbiome and host metabolism. Nat Commun 10, 4505.6.Zimmermann, M., Zimmermann-Kogadeeva, M., Wegmann, R., and Goodman, A.L. (2019). Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature 570, 462-467. The human intestinal microbiota has hundreds of different biochemical abilities. a single strain isolated from intestinal flora can metabolize dozens of drugs, but this phenomenon is rarely discussed and studied in the context of microbial community. here, we established a quantitative experimental scheme to test the ability of human intestinal microorganisms to metabolize small molecule drugs: screening of microbiome derived metabolism (MDM). it mainly includes the culture system for the continuous growth of intestinal microbial community, the in vitro drug metabolism screening system, and the screening and identification of microbial coding genes responsible for specific metabolic events by constructing a macro gene library. our study has clarified the relationship between new drug metabolism and microbial flora, which provides theoretical basis and application prospect for intestinal microbiome to be used in drug development and individualized medical treatment. The human gut microbiome harbors hundreds of bacterial species with diverse biochemical capabilities. Dozens of drugs have been shown to be metabolized by single isolates from the gut microbiome, but the extent of this phenomenon is rarely explored in the context of microbial communities. Here, we develop a quantitative experimental framework for mapping the ability of the human gut microbiome to metabolize small molecule drugs: Microbiome-Derived Metabolism (MDM)-Screen. Included are a batch culturing system for sustained growth of subject-specific gut microbial communities, an ex vivo drug metabolism screen, and targeted and untargeted functional metagenomic screens to identify microbiome-encoded genes responsible for specific metabolic events. Our framework identifies novel drug-microbiome interactions that vary between individuals and demonstrates how the gut microbiome might be used in drug development and personalized Wang Zuoyun, member of the youth Promotion Association of Chinese Academy of Sciences, associate researcher of the center for excellence and innovation of molecular cell science, Chinese Academy of Sciences (Shanghai Institute of Biochemistry and Cell Biology), Dr. Wang Zuoyun, member of youth innovation promotion association of Chinese Academy of Sciences (2018), branch of Chinese Academy of Sciences He is an associate researcher of the center for excellence and innovation in subcellular Science (Shanghai Institute of Biochemistry and Cell Biology). He is mainly engaged in the regulation mechanism of organ development and tissue homeostasis. 15 research papers have been published in EMBO journal, PLoS Genetics, cancer research, cancer letters, PLoS One, and the papers have been cited more than 300 times. it has successively won the project of China Postdoctoral fund and natural science of ChinaIt is supported by the youth program of NSFC, the excellent talents program of Chinese Academy of Sciences and the projects in Shanghai. Zuoyun Wang is an associate professor in Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology), Chinese Academy of Sciences (CAS). She was selected as a member (2018) of Youth Innovation Promotion Association of CAS. Her research mainly focuses on the functional and mechanistic study of carcinogenesis by integrative studies using human cancer cell lines, animal models and human cancer samples, especially the molecular and cellular mechanisms of Hippo pathway in organ development and tissue regeneration. She has been published 15 scientific papers such as EMBO Journal, PLoS Genetics, Cancer Research, Cancer Letters, PLoS One, which were cited over 300 times. She has received many foundation support including China Postdoctoral Science Foundation, National Natural Science Foundation of China, excellent talents program of CAS and foundation of Technology Commission of Shanghai Municipality,