The human body is colonized by microbes from all three domains of life, 43Dietary vitamin B1B1IL4+ILC2ILC2ILC2B1Tuft cellIL-4RIL-25IL-17RA/BGoblet cellIL-4with the gastrointestinal tract exhibiting the highest microbial density and diversity. Gut microbes outnumber their host by more than 25 times in terms of their genetic composition. This vast microbial ecosystem interacts intimately and, for the most part, mutually with the human host to perform essential met-abolic functions. Furthermore, metabolites generated through the interaction between a diverse range of dietary components and gut bacteria are influencing various systems within the host. While sequence-based microbiome-wide as-sociation studies provide correlative support for the notion that the microbiota influences human health and disease, they neither address the causality nor directionality of the host-microbiota relationship. Therefore, we are conducting causal studies to identify bacterial species that directly contribute to human ho-meostasis in specific ways. We have created an effective feedback cycle between bacterial isolation, generation of mutant bacterial strains, proteomic and me-tabolomic analyses combined with gnotobiotic studies. This will facilitate a de-tailed mechanistic understanding of the microbiota-mediated maintenance of homeostasis and multi-organ systems, where specific bacterial species and their products play causal roles. Ultimately, we hope to identify causally effective and therapeutically applicable minimal microbes and microbial products.In particular, our investigations have focused on the impact of gut bacteria and diet on the host’s immune system. Additionally, we have delved into the role of gut bacteria in gastrointestinal pathogen infections, metabolic disorders, and cancer, pinpointing specific bacterial populations that exert a significant influence on each of these conditions. This year, our research was particularly centered on exploring the connection between the differentiation of group 2 innate lymphoid cells (ILC2s), specifically IL-4- producing ILC2s, and dietary components. Moreover, we conducted a study on phage infections within the gut microbiota, which tend to become more prevalent with age.Figure: In the intestine, dietary vitamin B1 constitutively in-duces IL-4-expressing ILC2s that are dependent on Tuft cell-derived IL-25 signaling and contribute to mucus secretion.Recent Major PublicationsSoeda K, Sasako T, Enooku K, Kubota N, Kobayashi N, Ikushima YM, Awazawa M, Bouchi R, Toda G, Yamada T, Nakatsuka T, Tateishi R, Kakiuchi M, Yamamoto S, Tatsuno K, Atarashi K, Suda W, Honda K, Aburatani H, Ya-mauchi T, Fujishiro M, Noda T, Koike K, Kadowaki T, Ueki K. Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepati-tis. Nat Commun 14, 6584 (2023)Johansen J, Atarashi K, Arai Y, Hirose N, Sørensen SJ, Vatanen T, Knip M, Honda K, Xavier RJ, Rasmussen S, Plichta DR. Centenarians have a diverse gut virome with the potential to modulate metabolism and promote healthy lifespan. Nat Microbiol 8, 1064-1078 (2023)Cui W, Nagano Y, Morita S, Tanoue T, Yamane H, Ishikawa K, Sato T, Kubo M, Hori S, Taniguchi T, Hatakeyama M, Atarashi K, Honda K. Diet-mediated constitutive induction of novel IL-4+ ILC2 cells maintains intestinal homeostasis in mice. J Exp Med 220, e20221773 (2023)Invited presentationsHonda K. “Harness connections between the microbi-ome and disease to improve human health” SICS-OMICS Cancer Organoid Meeting (Tokyo, Japan) October 2023Honda K. “Toward the development of defined microbial therapeutics” EMBO/EMBL Symposium: The human microbiome (Heidelberg, Germany) September 2023Honda K. “Toward the development of defined microbial therapeutics” The 7th Microbiome R&D and Business Collaboration Congress Asia (Seoul, South Korea) Sep-tember 2023Honda K. “Toward the development of defined microbial therapeutics” at The Broad Institute of MIT and Harvard (Boston, USA) June 2023Laboratory for Gut HomeostasisTeam Leader: Kenya Honda
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