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Tokyo Medical and Dental University

Medical Research Institute

Department of Precision Health

Takahiro Adachi, Associate Professor, Joint Research Division

（Concurrent Post） Professor Hiroshi Nishina, Department of Developmental and Regenerative Biology

Atopy and developmental disorders in children, and lifestyle-related diseases are increasing, and dementia is becoming a social problem. It has been found that chronic inflammation caused by environmental factors other than genetic factors is a predisposition of diseases. It is pointed out that there is a correlation between mutual diseases. If we can detect the predisposition of diseases, we will be less burdened, and can prevent various diseases before their onset, resulting in extending healthy life. Recently, "pre-disease" is focused on a novel therapeutic target to maintain health. For that purpose, it is necessary to monitor biological information with high sensitivity and to develop a "prevention/treatment" method for the predisposition of diseases. Therefore, we are working on research aimed at developing preventive and therapeutic methods by detecting slight abnormalities in the body more quickly and easily.

Analysis of immune response

We have generated a cell lineage-specific calcium biosensor (YC3.60) mouse that can monitor not only the dynamics of immune cells but also activation in vivo, and established a 6D (x, y, z, time, Ca2+ signaling, cell labeling) intravital imaging system. Using this system, it is possible to visualize the activation and differentiation of immune cells in the living body in real-time. We have also found that bioimaging focusing on intracellular Ca2+ signaling using these mice can detect the predisposition of diseases at a very early phase before developing the pathological disorders. We are trying to further develop this system and to clarify the onset of various diseases such as allergies, viral infections, and autoimmune diseases, and the detailed events occurring in the process of pathological progress.

Highlight

The most abundant immunoglobulin (antibody) in our body is immunoglobulin A (IgA), and it has been known that IgA is secreted into the intestinal lumen and is important for the elimination of pathogens. However, although selective IgA deficiency is the most common in human immunodeficiency, no serious symptoms were observed. Thus, the precise function of IgA remains unclear. We have generated IgA-deficient mice, and found that in these mice, the intestinal flora of the small intestine was distorted, and an excessive immune cell activation especially in the ileum, causing ileal inflammation. Thus, IgA contributes to the homeostasis of the intestinal flora of the ileum to prevent inflammation.

(Gut 2022, https://www.tmd.ac.jp/english/press-release/20210527-1/, https://www.youtube.com/watch?v=Z8OYt-9BUSg)

No IgA leads to intestinal inflammation in mice by Takahiro Adachi｜Tokyo Medical and Dental University, National University Corporation (tmd.ac.jp)

2. Analysis of intestinal sensing network and organ linkage

The immune system, peripheral nervous system, and endocrine system are concentrated in the intestinal tract, and information is directly exchanged by the brain-gut axis. To clarify how foods, medicines, etc. orally ingested are recognized in the intestinal tract, we have established intravital imaging of the enteric nervous system, immune cells, or enteric epithelial cells in a cell-specific manner. Based on these established technologies, we are trying to clarify the mechanisms of the intestinal sensing network and the crosstalk such as the gut-brain mediated by orally administrated-food and medicine. We also analyze other crosstalk such as the gut-skin axis.

3. Establishment of prevention/treatment methods for predisposition of diseases and methods to increase robustness for health

We aim to develop foods and medicines that target the predisposition of diseases, as well as foods and medicines that enhance robustness to maintain physical and mental health. We evaluate the effects of foods, natural products, and their components on the immune system, nervous system, and intestinal epithelium including endocrine. We are developing preventive/therapeutic methods and robustness acquisition methods using a model mouse system that has an abnormality or predisposition of diseases in the intestinal/skin barrier function and a dietary obese mouse model system.

4.Clinical application for monitoring of predisposition of diseases

We aim to establish a method for detecting slight changes (predisposition of diseases) before the onset of diseases and try to develop foods and medicine to prevent and treat these disorders. Based on these basic researches, we are trying to develop a device that can easily measure slight abnormalities that predispose to diseases such as lifestyle-related diseases and developmental disorders in humans for clinical application.

Publications

Kotake, K., Kumazawa, T, Adachi, T. Long-term administration of Tetragenococcus halophilus No. 1 over generations affects the immune system of mice. PLoS One, 17(4):e0267473. 2022. (IF=3.240)

Published: April 26, 2022 https://doi.org/10.1371/journal.pone.0267473

Hirata Y, Nomura K, Kato D, Tachibana Y, Niikura T, Uchiyama K, Hosooka T, Fukui T, Oe K, Kuroda R, Hara Y, Adachi , Shibasaki K, Wake H, and Ogawa W. A Piezo1/KLF15/IL-6 axis mediates immobilization-induced muscle atrophy. J Clin Invest. https://doi.org/10.1172/JCI154611.(IF=14.808)

Gao P, Adachi T, Okai S, Morita N, Kitamura D, Shinkura R. Integrin CD11b provides a new marker of pre-germinal center IgA + B cells in murine Peyer's patches. Int Immunol. 2021 Dec 31:dxab113.

doi: 10.1093/intimm/dxab113. Online ahead of print.PMID: 34971392 (IF=4.823)

Kotake, K., Kumazawa, T, Nakamura, K, Shimizu, Y, Ayabe , T., Adachi, T. Ingestion of miso regulates immunological robustness in mice. PLoS One, 17(1):e0261680. 2022. (IF=3.240)

Nagaishi, T., Watabe, T., Kotake, K., Kumazawa, T., Aida, T., Tanaka, K., Ono, R., Ishino, F., Usami, T., Miura, T., Hirakata, S., Kawasaki, H., Tsugawa, N., Yamada, D., Hirayama, K., Yoshikawa, S., Karasuyama, H., Okamoto, R., Watanabe, M., *Blumberg, R.S., and *Adachi, T., Immunoglobulin A-specific deficiency induces spontaneous inflammation specifically in the ileum. Gut. 2021. (IF=23.059)

Tsugawa, N., Yamada, D., Watabe, T., Onizawa, M., Wang, S., Nemoto, Y., Oshima, S., Tsubata, T., Adachi, T., Kawano, Y., Watanabe, M., Blumberg, R.S., Okamoto, R., and *Nagaishi, T., CEACAM1 specifically suppresses B cell receptor signaling-mediated activation. Biochem Biophys Res Commun, 535: 99-105. 2021. (IF=3.575)

Yokoi, Y., Adachi, T., Sugimoto, R., Kikuchi, M., Ayabe, T., and *Nakamura, K., Simultaneous real-time analysis of Paneth cell and intestinal stem cell response to interferon-gamma by a novel stem cell niche tracking method. Biochem Biophys Res Commun, 545: 14-9. 2021. (IF=3.575)

Endo, R., Uchiyama, K., Lim, S.Y., Itakura, M., Adachi, T., and *Uchida, K., Recognition of acrolein-specific epitopes by B cell receptors triggers an innate immune response. J Biol Chem: 100648. 2021. (IF=4.238)

Yasuda, K., *Nakashima, A., Murata, A., Suzuki, K., and *Adachi, T., Euglena Gracilis and beta-Glucan Paramylon Induce Ca(2+) Signaling in Intestinal Tract Epithelial, Immune, and Neural Cells. Nutrients, 12. 2020. (IF=4.546)

Nishimura, Y., Fukuda, Y., Okonogi, T., Yoshikawa, S., Karasuyama, H., Osakabe, N., Ikegaya, Y., *Sasaki, T., and *Adachi, T., Dual real-time in vivo monitoring system of the brain-gut axis. Biochem Biophys Res Commun, 524: 340-5. 2020. (IF=3.575)

Kumazawa, T., Kotake, K., Nishimura, A., Asai, N., Ugajin, T., Yokozeki, H., and *Adachi, T., Isolation of food-derived bacteria inducing interleukin-22 in B cells. Biosci Microbiota Food Health, 39: 1-9. 2020. (IF=3.121)

Isobe, J., Maeda, S., Obata, Y., Iizuka, K., Nakamura, Y., Fujimura, Y., Kimizuka, T., Hattori, K., Kim, Y.G., Morita, T., Kimura, I., Offermanns, S., Adachi, T., Nakao, A., Kiyono, H., Takahashi, D., and *Hase, K., Commensal-bacteria-derived butyrate promotes the T-cell-independent IgA response in the colon. Int Immunol, 32: 243-58. 2020. (IF=3.519)

Aihara, Y., Fukuda, Y., Takizawa, A., Osakabe, N., Aida, T., Tanaka, K., Yoshikawa, S., Karasuyama, H., and *Adachi, T., Visualization of mechanical stress-mediated Ca(2+) signaling in the gut using intravital imaging. Biosci Microbiota Food Health, 39: 209-18. 2020. (IF=3.121)

*Yoshikawa, S., Oh-Hora, M., Hashimoto, R., Nagao, T., Peters, L., Egawa, M., Ohta, T., Miyake, K., Adachi, T., Kawano, Y., Yamanishi, Y., and Karasuyama, H., Pivotal role of STIM2, but not STIM1, in IL-4 production by IL-3-stimulated murine basophils. Sci Signal, 12. 2019. (IF=6.467)

Fujii, Y., Suzuki, K., Adachi, T., Taira, S., and *Osakabe, N., Corticotropin-releasing hormone is significantly upregulated in the mouse paraventricular nucleus following a single oral dose of cinnamtannin A2 as an (-)-epicatechin tetramer. J Clin Biochem Nutr, 65: 29-33. 2019. (IF=2.405)

*Adachi, T., Yoshikawa, S., Tezuka, H., Tsuji, N.M., Ohteki, T., Karasuyama, H., and Kumazawa, T., Propolis induces Ca(2+) signaling in immune cells. Biosci Microbiota Food Health, 38: 141-9. 2019. (IF=3.121)

Watabe, T., Nagaishi, T., Tsugawa, N., Kojima, Y., Jose, N., Hosoya, A., Onizawa, M., Nemoto, Y., Oshima, S., Nakamura, T., Karasuyama, H., Adachi, T., and *Watanabe, M., B cell activation in the cecal patches during the development of an experimental colitis model. Biochem Biophys Res Commun, 496: 367-73. 2018. (IF=2.705)

Tabakawa, Y., Ohta, T., Yoshikawa, S., Robinson, E.J., Yamaji, K., Ishiwata, K., Kawano, Y., Miyake, K., Yamanishi, Y., Ohtsu, H., Adachi, T., Watanabe, N., Kanuka, H., and *Karasuyama, H., Histamine Released From Skin-Infiltrating Basophils but not mast cells is crucial for acquired tick resistance in mice. Front Immunol, 9: 1540. 2018. (IF=4.716)

Nakagawa, Y., Ishimura, K., Oya, S., Kamino, M., Fujii, Y., Nanba, F., Toda, T., Ishii, T., Adachi, T., Suhara, Y., and *Osakabe, N., Comparison of the sympathetic stimulatory abilities of B-type procyanidins based on induction of uncoupling protein-1 in brown adipose tissue (BAT) and increased plasma catecholamine (CA) in mice. PLoS One, 13: e0201203. 2018. (IF=2.776)

*Lino, A.C., *Dang, V.D., *Lampropoulou, V., *Welle, A., Joedicke, J., Pohar, J., Simon, Q., Thalmensi, J., Baures, A., Fluhler, V., Sakwa, I., Stervbo, U., Ries, S., Jouneau, L., Boudinot, P., Tsubata, T., Adachi, T., Hutloff, A., Dorner, T., Zimber-Strobl, U., de Vos, A.F., Dahlke, K., Loh, G., Korniotis, S., Goosmann, C., Weill, J.C., Reynaud, C.A., Kaufmann, S.H.E., Walter, J., and *Fillatreau, S., LAG-3 Inhibitory Receptor Expression Identifies Immunosuppressive Natural Regulatory Plasma Cells. Immunity, 49: 120-33 e9. 2018. (IF=21.522)

Kumazawa, T., Nishimura, A., Asai, N., and *Adachi, T., Isolation of immune-regulatory Tetragenococcus halophilus from miso. PLoS One, 13: e0208821. 2018. (IF=2.776)

Jin, K., Imada, T., Nakamura, S., Izuta, Y., Oonishi, E., Shibuya, M., Sakaguchi, H., Adachi, T., and *Tsubota, K., Intravital Two-photon Imaging of Ca(2+) signaling in Secretory Organs of Yellow Cameleon Transgenic Mice. Sci Rep, 8: 15880. 2018. (IF=4.011)

Fujii, Y., Suzuki, K., Hasegawa, Y., Nanba, F., Toda, T., Adachi, T., Taira, S., and *Osakabe, N., Single oral administration of flavan 3-ols induces stress responses monitored with stress hormone elevations in the plasma and paraventricular nucleus. Neurosci Lett, 682: 106-11. 2018. (IF=2.173)

Yoshikawa, S., Usami, T., Kikuta, J., Ishii, M., Sasano, T., Sugiyama, K., Furukawa, T., Nakasho, E., Takayanagi, H., Tedder, T.F., Karasuyama, H., Miyawaki, A., and *Adachi, T., Intravital imaging of Ca(2+) signals in lymphocytes of Ca(2+) biosensor transgenic mice: indication of autoimmune diseases before the pathological onset. Sci Rep, 6: 18738. 2016. (IF=4.259)

Akatsu, C., Shinagawa, K., Numoto, N., Liu, Z., Ucar, A.K., Aslam, M., Phoon, S., Adachi, T., Furukawa, K., Ito, N., and *Tsubata, T., CD72 negatively regulates B lymphocyte responses to the lupus-related endogenous toll-like receptor 7 ligand Sm/RNP. J Exp Med, 213: 2691-706. 2016. (IF=11.991)

*Adachi, T., Kakuta, S., Aihara, Y., Kamiya, T., Watanabe, Y., Osakabe, N., Hazato, N., Miyawaki, A., Yoshikawa, S., Usami, T., Karasuyama, H., Kimoto-Nira, H., *Hirayama, K., and *Tsuji, N.M., Visualization of Probiotic-Mediated Ca(2+) Signaling in Intestinal Epithelial Cells In Vivo. Front Immunol, 7: 601. 2016. (IF=6.429)