Fujimoto Lab／Division of Infectious Disease  Department of Microbial Regulation

Research Overview

Advancements in next-generation sequencing technologies have greatly improved the precision, scope, and speed of metagenomic analyses, and have enabled the identification of numerous critical links between human diseases and symbiotic pathogenic bacteria (pathobionts). Within this technological context, our research seeks to clarify the mechanisms driving the onset of various diseases, including immune disorders, by developing a detailed understanding of the human microbiome.

Progress in this field also requires the training of hybrid researchers skilled in both experimental (wet) and computational (dry) approaches. We are therefore dedicated to cultivating the next generation of interdisciplinary researchers to further advance microbial control science.

1) Identification of Key Microorganisms Linking Commensal Microbiota to Human Disease

Dysbiosis of the commensal microbiota is increasingly recognized as a factor contributing to the onset and progression of human diseases. In particular, specific disease-associated “key microorganisms (or groups)” are believed to play central roles in pathogenesis. Previous studies by our lab have identified pathobionts linked to distinct conditions, including Thomasclavelia ramosa (formerly Clostridium ramosum), which is linked to obesity and diabetes (Gastroenterology, 2019), Enterococcus faecalis, linked to graft-versus-host disease (Nature, 2024), and Staphylococcus hominis, linked to axillary osmidrosis (J Invest Dermatol, 2024).

Microbial communities such as the gut microbiota form complex ecosystems in which constituent microorganisms complement one another functionally. Thus, clarifying the “functions” of individual microbes, rather than only describing compositional changes, is essential to understanding the relationship between microbiota and disease.

Since 1945, when Reyniers developed germ-free animal housing systems, it has become possible to use germ-free and gnotobiotic animals colonized with defined microbial communities. In our laboratory, we combine state-of-the-art metagenomic techniques with gnotobiotic animal models to functionally characterize pathobionts and to design novel microbiota-targeted strategies for disease control. In addition, we apply advanced approaches such as single-cell microbial analysis to examine the diversity, function, and ecological interactions of archaea within the gut microbiome.

2) Developing Disease Control Strategies Using Phage-Derived Lytic Enzymes

At present, we are developing therapeutic approaches that target disease-associated pathobionts with phage-derived lytic enzymes exhibiting high bacterial specificity. Our earlier studies demonstrated the efficacy of endolysins—enzymes that cleave peptidoglycan, a major component of Gram-positive bacterial cell walls (Cell Host Microbe, 2020; J Invest Dermatol, 2024; Nature, 2024).

To expand these findings to multidrug-resistant bacteria, we aim to construct a diverse library of functional endolysins. Gram-negative bacteria, however, pose a greater challenge because their outer membrane contains a lipopolysaccharide (LPS) layer that blocks conventional endolysins. To overcome such limitations, we are searching for enzymes able to degrade or penetrate the LPS barrier, using metagenomic data to identify candidates.
 

Phage-derived lytic enzymes, through their specificity and rapid activity, show strong potential not only for combating antibiotic resistance and treating infections but also as molecular tools for controlling diseases mediated by specific microbial players.

3) Translational Research Toward Clinical Implementation of Phage Therapies

Although phage therapy is not yet approved in Japan, it is attracting global attention as a promising countermeasure against antimicrobial-resistant bacteria. Moreover, industry–academic collaborations have facilitated the development of endolysin-based formulations targeting Enterococcus faecalis.

In April 2024, we launched Japan’s first clinical trial of phage therapy (jRCTs051230164), a major step toward linking basic research with clinical application. Significant challenges to implementation remain, however, including the creation of manufacturing systems and clinical trial protocols for phage preparations.

To overcome these obstacles, we are building an integrated framework that spans basic research, formulation development, preclinical evaluation, and clinical trials, in collaboration with domestic and international phage researchers and related institutions. Through this approach, we aim to support the practical implementation and broader adoption of phage therapy in Japan.