This strategic proposal is to propose various measures to create new health care and medical technologies based on the concept of microbiome present in human epithelium (e.g., oral cavity, gastrointestinal tract, skin, respiratory tract, and reproductive organs), and to deepen understanding of life and diseases with world's top-level researches and technologies in Japan.

<Social trends and expectations for health care and medical technology> :
With low birth rate and rapidly increasing aging population, medical care and elderly care cost keep growing every year in Japan by increased needs for those cares as well as advances in medical technology. There are many unmet medical needs; the important challenge and rising expectation in the pharmaceutical industry is to improve the success rate of new drug discovery and to explore the new concept of drug discovery. The future direction for the ideal health care and medical technology is with high cost-effectiveness (e.g., drugs), preventive technologies based on sufficient evidence (e.g., diet, exercise), and diagnostic technology to provide those technologies to people who benefit from them the most (e.g., evaluation of health condition, disease diagnosis, subgrouping). In order to realize them, althohugh there are wide-ranging research themes to be promoted, human microbiome (*) has a particular significance to be implemented in a top-down manner in Japan, through the overview survey of Center for Research and Development Strategy (CRDS), Japan Science and Technology Agency (JST).

(*) What is "Microbiome"?:
The microbiome refers to enormous kinds and amounts of microorganisms (e.g., bacteria, fungi, viruses, and so on) present in various places in the globe (e.g., animals/plants, soil, ocean, atomosphere,living environment). In humans, they are present in the epithelium of the entire body (oral cavity, respiratory tract, gastrointestinal tract, skin, reproductive organs). For example, there are reportedly approximately 1,000 kinds of enterobacteria in humans, 100 trillion bacterial cells, with the weight of approximately 1.0～1.5 kg, and with approximately 0.5 million genes (there are 20,000 human genes). It has been suggested one after another that enterobacteria play various roles in the body, such as nutrient supply (energy [e.g., butyric acid], vitamins) regulation of the immunity and metabolic systems in a symbiotic relationship.

< Microbiome-related research trend>：
Microbiome research was actively promoted in the 1960s in Japan and abroad; in Japan, Dr. Tomotari Mitsuoka achieved the significant results that attracted major attention from around the world in culturing technology of hardly culturable microorganism and phylogenic system classification of microorganisms (e.g., good bacteria, bad bacteria). However, with the technology available in those days, it was difficult to elucidate the whole picture of microbiome, and subsequent progress of the research was gradual. Such situation was changed substantially by the launch of the next-generation sequencer in 2005 and the development and popularization of metagenome analysis technology (Analysis of structure of microbiome from its genetic information) associated with it. In 2008, a large-scale project of microbiome started in Europe and the United States, which promoted the establishment of the fundamental information required for the execution of microbiome studies (e.g., information of genome sequence of microorganisms, data from healthy Europeans/Americans) and identified correlation between various diseases and the condition of enterobacteria in humans. In 2013, fecal transplantation treatment was proven effective, where feces from healthy human were transplanted in patients, making the development of treatment focusing on enterobacterial flora progresses from possibility to actuality. In recent years, the identification of groups of microorganisms responsible for the efficacy of treatment is underway; furthermore, individual functional molecules may be identified. Gradually, human microbiome is becoming increasingly expected as a future seeds for drug discovery in the industry.

< Technological superiority of Japan> :
We are now in the stage to make a step forward from the stage of elucidation of correlation between microbiome and the host (humans) to promote the understanding of detailed mechanism, or accelerate preventive medicine with a focus on functional molecules to act on the host (humans) or their receptors and the development of treatment technology. We have world's top-level strength in many of the technologies and research fields required for them. For example, enormous amount of know-hows and skillful technologies are accumulated in Japan for culturing technologies for hardly culturable microorganism and gnotobiotic technology (technology to transplant certain microorganisms in sterilized animals). We have superior analysis technology/system for metabolomic analysis (technology to analyze metabolites comprehensively) in Japan. Due to technical difficulty, sampling from the small intestine is not performed in Europe and the United States; however, sampling is possible in Japan thanks to the presence of many clinicians experienced in endoscopy. In addition, we conduct world top-level life-science researches of immunology, imaging, and epigenome required in the understanding of life phenomena related to microbiome and pathogenic mechanism. < Priority research and development themes> :
The following are research and development themes required to promote deep understanding of microbiome-host interaction and develop health care and medical technology ahead of other countries through maximally utilizing the strength of Japan.

(1) Establishment of core technologies for operation, culturing, and analysis of microbiome
Culturing technology for hardly culturable microorganisms, in vivo analysis technology of microbiome function (e.g., gnotobiote), sampling technology (e.g., enteroscopy), metagenome/metatranscriptome analysis technology, metabolome analysis technology

(2) Collection and analysis of related information
Collection and analysis of data of healthy Japanese, epidemiological research

(3) Research of life, health, and disease science
Life science/health and disease science [Research fields] immunology, nutrition, metabolism, host genome/epigenome, and imaging; [Research target] health condition (e.g., nutrition), psychiatric and neurological disorder, autoimmune disease, lifestyle related diseases, cancer, infectious diseases), data science (database building and integrated analysis)

(4) Development of health and medical technology
Diagnostic technology (evaluation of health condition, disease diagnosis), treatment technology (e.g., microorganism cocktail, drugs), preventive technology (e.g., diet, exercise)

< Promotion method> :
In order to maximize the results which are generated through the promotion of research and development themes described earlier, efforts such as consolidation and centralization of technology and information and environment development toward social implementation are required. For example, consolidation and centralization are expected to lead to effective and efficient support and further advances of technology and knowhow for culture technology for hardly culturable microorganisms, gnotobiote technology, metagenome analysis technology, and metabolomic analysis technology. Centralized collection and analysis of data of healthy Japanese required as comparative control in disease studies is expected to improve data quality, leading to its wider use. Since microbiome is very complex, a data science-based approach (e.g., integrated analysis of data, system biology) is highly important in its elucidation, and the establishment of database centers is required to accumulate enormous amount of data groups obtained through related research activities in a format that can be analyzed in an integrated manner. These centers are ideally developed through the utilization of organizations and research laboratories with knowhow, technology, and equipment.

The establishment of a head office is also needed, which grasps all these conditions and strategically promotes microbiome research in Japan. The head office will grasp the trend of microorganism research in Japan and abroad; respond to research protocol standardization (sampling, storage, pretreatment, analysis) and protection of personal information; establish and maintain research environment such as promotion of regulatory science (evaluation science of efficacy and safety); give advice to promising research seeds in terms of intellectual property; and accelerate bridging to corporations (e.g., pharmaceutical, food).

< Temporal axis> :
First, governmental investment in research and development of human microbiome should be started as soon as possible; in parallel, the technologies required in the promotion of these researches should be integrated and centralized, while utilizing existing organizations and research laboratories. With regard to the data of healthy Japanese, discussion should be started on the size of data and items to be collected, a collection/analysis system should be established quickly, and intensive promotion of the information base toward development of health and medical technology should be done. Sufficiently validate whether the candidates for medical technology seeds identified through these efforts are appropriate as medical technology and conduct clinical studies to implement them in the society. With regard to preventive technology seeds (diet, exercise), sufficient scientific evidence should be established and the commercialization of products should be promoted according to the rules in Japan and abroad. Although the number of researchers in this field is limited at this point, participation of researchers in surrounding fields is expected by research and development investment. Since human microbiome is related to various life phenomena and diseases, the layer of potential researchers is considered to rapidly expand in the future, and a larger-scale research and development investment is expected in the future. "Complex life/health/disease science" is a new framework that is expected to connect existing research frameworks (e.g., cancer, regenerative medicine) and achieve a major breakthrough; human microbiome research is considered to be an important theme with a role in it.

< Spin-off benefit> :
The promotion of this strategic proposal has strong significance in terms of social needs fulfillment and academia. From the viewpoints of safety, efficacy, and economic efficiency, more and more subgroups of patients will emerge to whom medical technology is provided. The focus on difference in microbiome can realize the formation of more detailed subgroups. Changes in microbiome are considered to occur prior to the onset of disease and progression to severe disease; therefore, its research will lead to the prevention of onset and development of technology to prevent progression to severe disease. As a result, it can contribute to the optimization of medical care and elderly care cost. In addition, human microbiome research may achieve a breakthrough for pathologies without sufficient treatment, contributing to the activation of the pharmaceutical industry. The food industry is also expected to be activated by the development of evidence-based food and sharing appropriate information with consumers. The research base for microbiome established through the promotion of this strategic proposal can be utilized in the researches of non-human microbiome (e.g., plants, livestock, pets, soil, atomosphere, ocean, living space). It is considered that various fields including food production technology will make a major progress through microbiome research.