論文 - 本田　賢也

IL-10 produced by macrophages regulates epithelial integrity in the small intestine

Morhardt T., Hayashi A., Ochi T., Quirós M., Kitamoto S., Nagao-Kitamoto H., Kuffa P., Atarashi K., Honda K., Kao J., Nusrat A., Kamada N.

Scientific Reports （Scientific Reports）  9 （ 1 ）  2019年12月

　概要を見る

© 2019, The Author(s). Macrophages (Mϕs) are known to be major producers of the anti-inflammatory cytokine interleukin-10 (IL-10) in the intestine, thus playing an important role in maintaining gastrointestinal homeostasis. Mϕs that reside in the small intestine (SI) have been previously shown to be regulated by dietary antigens, while colonic Mϕs are regulated by the microbiota. However, the role which resident Mϕs play in SI homeostasis has not yet been fully elucidated. Here, we show that SI Mϕs regulate the integrity of the epithelial barrier via secretion of IL-10. We used an animal model of non-steroidal anti-inflammatory drug (NSAID)-induced SI epithelial injury to show that IL-10 is mainly produced by MHCII+ CD64+ Ly6Clow Mϕs early in injury and that it is involved in the restoration of the epithelial barrier. We found that a lack of IL-10, particularly its secretion by Mϕs, compromised the recovery of SI epithelial barrier. IL-10 production by MHCII+ CD64+ Ly6Clow Mϕs in the SI is not regulated by the gut microbiota, hence depletion of the microbiota did not influence epithelial regeneration in the SI. Collectively, these results highlight the critical role IL-10-producing Mϕs play in recovery from intestinal epithelial injury induced by NSAID.

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Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis

Nakamoto N., Sasaki N., Aoki R., Miyamoto K., Suda W., Teratani T., Suzuki T., Koda Y., Chu P., Taniki N., Yamaguchi A., Kanamori M., Kamada N., Hattori M., Ashida H., Sakamoto M., Atarashi K., Narushima S., Yoshimura A., Honda K., Sato T., Kanai T.

Nature Microbiology （Nature Microbiology）  4 （ 3 ） 492 - 503 2019年03月

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© 2019, The Author(s), under exclusive licence to Springer Nature Limited. Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and its frequent complication with ulcerative colitis highlights the pathogenic role of epithelial barrier dysfunction. Intestinal barrier dysfunction has been implicated in the pathogenesis of PSC, yet its underlying mechanism remains unknown. Here, we identify Klebsiella pneumonia in the microbiota of patients with PSC and demonstrate that K. pneumoniae disrupts the epithelial barrier to initiate bacterial translocation and liver inflammatory responses. Gnotobiotic mice inoculated with PSC-derived microbiota exhibited T helper 17 (T H 17) cell responses in the liver and increased susceptibility to hepatobiliary injuries. Bacterial culture of mesenteric lymph nodes in these mice isolated K. pneumoniae, Proteus mirabilis and Enterococcus gallinarum, which were prevalently detected in patients with PSC. A bacterial-organoid co-culture system visualized the epithelial-damaging effect of PSC-derived K. pneumoniae that was associated with bacterial translocation and susceptibility to T H 17-mediated hepatobiliary injuries. We also show that antibiotic treatment ameliorated the T H 17 immune response induced by PSC-derived microbiota. These results highlight the role of pathobionts in intestinal barrier dysfunction and liver inflammation, providing insights into therapeutic strategies for PSC.

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A defined commensal consortium elicits CD8 T cells and anti-cancer immunity

Tanoue T., Morita S., Plichta D., Skelly A., Suda W., Sugiura Y., Narushima S., Vlamakis H., Motoo I., Sugita K., Shiota A., Takeshita K., Yasuma-Mitobe K., Riethmacher D., Kaisho T., Norman J., Mucida D., Suematsu M., Yaguchi T., Bucci V., Inoue T., Kawakami Y., Olle B., Roberts B., Hattori M., Xavier R., Atarashi K., Honda K.

Nature （Nature）  565 （ 7741 ） 600 - 605 2019年01月

ISSN  00280836

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© 2019, Springer Nature Limited. There is a growing appreciation for the importance of the gut microbiota as a therapeutic target in various diseases. However, there are only a handful of known commensal strains that can potentially be used to manipulate host physiological functions. Here we isolate a consortium of 11 bacterial strains from healthy human donor faeces that is capable of robustly inducing interferon-γ-producing CD8 T cells in the intestine. These 11 strains act together to mediate the induction without causing inflammation in a manner that is dependent on CD103 + dendritic cells and major histocompatibility (MHC) class Ia molecules. Colonization of mice with the 11-strain mixture enhances both host resistance against Listeria monocytogenes infection and the therapeutic efficacy of immune checkpoint inhibitors in syngeneic tumour models. The 11 strains primarily represent rare, low-abundance components of the human microbiome, and thus have great potential as broadly effective biotherapeutics.

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Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid

Morita H., Kubo T., Rückert B., Ravindran A., Soyka M., Rinaldi A., Sugita K., Wawrzyniak M., Wawrzyniak P., Motomura K., Tamari M., Orimo K., Okada N., Arae K., Saito K., Altunbulakli C., Castro-Giner F., Tan G., Neumann A., Sudo K., O'Mahony L., Honda K., Nakae S., Saito H., Mjösberg J., Nilsson G., Matsumoto K., Akdis M., Akdis C.

Journal of Allergy and Clinical Immunology （Journal of Allergy and Clinical Immunology）  2019年

ISSN  00916749

　概要を見る

© 2019 American Academy of Allergy, Asthma & Immunology Background: Group 2 innate lymphoid cells (ILC2s) play critical roles in induction and exacerbation of allergic airway inflammation. Thus clarification of the mechanisms that underlie regulation of ILC2 activation has received significant attention. Although innate lymphoid cells are divided into 3 major subsets that mirror helper effector T-cell subsets, counterpart subsets of regulatory T cells have not been well characterized. Objective: We sought to determine the factors that induce regulatory innate lymphoid cells (ILCregs). Methods: IL-10 + ILCregs induced from ILC2s by using retinoic acid (RA) were analyzed with RNA-sequencing and flow cytometry. ILCregs were evaluated in human nasal tissue from healthy subjects and patients with chronic rhinosinusitis with nasal polyps and lung tissue from house dust mite– or saline-treated mice. Results: RA induced IL-10 secretion by human ILC2s but not type 2 cytokines. IL-10 + ILCregs, which were converted from ILC2s by means of RA stimulation, expressed a regulatory T cell–like signature with expression of IL-10, cytotoxic T lymphocyte–associated protein 4, and CD25, with downregulated effector type 2–related markers, such as chemoattractant receptor–homologous molecule on T H 2 cells and ST2, and suppressed activation of CD4 + T cells and ILC2s. ILCregs were rarely detected in human nasal tissue from healthy subjects or lung tissue from saline-treated mice, but numbers were increased in nasal tissue from patients with chronic rhinosinusitis with nasal polyps and in lung tissue from house dust mite–treated mice. Enzymes for RA synthesis were upregulated in airway epithelial cells during type 2 inflammation in vivo and by IL-13 in vitro. Conclusion: We have identified a unique immune regulatory and anti-inflammatory pathway by which RA converts ILC2s to ILCregs. Interactions between airway epithelial cells and ILC2s play an important roles in the generation of ILCregs.

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Mining the microbiota for microbial and metabolite-based immunotherapies

Skelly A., Sato Y., Kearney S., Honda K.

Nature Reviews Immunology （Nature Reviews Immunology）  2019年

ISSN  14741733

　概要を見る

© 2019, The Author(s), under exclusive licence to Springer Nature Limited. Trillions of microorganisms transit through and reside in the mammalian gastrointestinal tract each day, collectively producing thousands of small molecules and metabolites with local and systemic effects on host physiology. Identifying effector microorganisms that causally affect host phenotype and deciphering the underlying mechanisms have become foci of microbiome research and have begun to enable the development of microbiota-based therapeutics. Two complementary, reductionist approaches have commonly been used: the first starts with an immune phenotype and narrows down the microbiota to identify responsible effector bacteria, while the second starts with bacteria-derived molecules and metabolites and seeks to understand their effects on the host immune system. Together, these strategies provide the basis for the rational design of microbial and metabolite-based therapeutics that target and ameliorate immune deficits in patients.

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Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis

Ladinsky M., Araujo L., Zhang X., Veltri J., Galan-Diez M., Soualhi S., Lee C., Irie K., Pinker E., Narushima S., Bandyopadhyay S., Nagayama M., Elhenawy W., Coombes B., Ferraris R., Honda K., Iliev I., Gao N., Bjorkman P., Ivanov I.

Science （Science）  363 （ 6431 ）  2019年

ISSN  00368075

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2017 © The Authors. Commensal bacteria influence host physiology, without invading host tissues. We show that proteins from segmented filamentous bacteria (SFB) are transferred into intestinal epithelial cells (IECs) through adhesion-directed endocytosis that is distinct from the clathrin-dependent endocytosis of invasive pathogens. This process transfers microbial cell wall–associated proteins, including an antigen that stimulates mucosal T helper 17 (T H 17) cell differentiation, into the cytosol of IECs in a cell division control protein 42 homolog (CDC42)–dependent manner. Removal of CDC42 activity in vivo led to disruption of endocytosis induced by SFB and decreased epithelial antigen acquisition, with consequent loss of mucosal T H 17 cells. Our findings demonstrate direct communication between a resident gut microbe and the host and show that under physiological conditions, IECs acquire antigens from commensal bacteria for generation of T cell responses to the resident microbiota.

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Computer-guided design of optimal microbial consortia for immune system modulation

Stein R., Tanoue T., Szabady R., Bhattarai S., Olle B., Norman J., Suda W., Oshima K., Hattori M., Gerber G., Sander C., Honda K., Bucci V.

eLife （eLife）  7 2018年04月

　概要を見る

© Stein et al. Manipulation of the gut microbiota holds great promise for the treatment of diseases. However, a major challenge is the identification of therapeutically potent microbial consortia that colonize the host effectively while maximizing immunologic outcome. Here, we propose a novel workflow to select optimal immune-inducing consortia from microbiome compositicon and immune effectors measurements. Using published and newly generated microbial and regulatory T-cell (T reg ) data from germ-free mice, we estimate the contributions of twelve Clostridia strains with known immune-modulating effect to T reg induction. Combining this with a longitudinal data-constrained ecological model, we predict the ability of every attainable and ecologically stable subconsortium in promoting T reg activation and rank them by the T reg Induction Score (TrIS). Experimental validation of selected consortia indicates a strong and statistically significant correlation between predicted TrIS and measured T reg . We argue that computational indexes, such as the TrIS, are valuable tools for the systematic selection of immune-modulating bacteriotherapeutics.

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Clarithromycin expands CD11b⁺Gr-1⁺cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia

Namkoong H., Ishii M., Fujii H., Yagi K., Asami T., Asakura T., Suzuki S., Hegab A., Kamata H., Tasaka S., Atarashi K., Nakamoto N., Iwata S., Honda K., Kanai T., Hasegawa N., Koyasu S., Betsuyaku T.

PLoS Pathogens （PLoS Pathogens）  14 （ 4 ）  2018年04月

ISSN  15537366

　概要を見る

© 2018 Namkoong et al. Macrolides are used to treat various inflammatory diseases owing to their immunomodulatory properties; however, little is known about their precise mechanism of action. In this study, we investigated the functional significance of the expansion of myeloid-derived suppressor cell (MDSC)-like CD11b+Gr-1+cells in response to the macrolide antibiotic clarithromycin (CAM) in mouse models of shock and post-influenza pneumococcal pneumonia as well as in humans. Intraperitoneal administration of CAM markedly expanded splenic and lung CD11b+Gr-1+cell populations in naïve mice. Notably, CAM pretreatment enhanced survival in a mouse model of lipopolysaccharide (LPS)-induced shock. In addition, adoptive transfer of CAM-treated CD11b+Gr-1+cells protected mice against LPS-induced lethality via increased IL-10 expression. CAM also improved survival in post-influenza, CAM-resistant pneumococcal pneumonia, with improved lung pathology as well as decreased interferon (IFN)-γ and increased IL-10 levels. Adoptive transfer of CAM-treated CD11b+Gr-1+cells protected mice from post-influenza pneumococcal pneumonia. Further analysis revealed that the CAM-induced CD11b+Gr-1+cell expansion was dependent on STAT3-mediated Bv8 production and may be facilitated by the presence of gut commensal microbiota. Lastly, an analysis of peripheral blood obtained from healthy volunteers following oral CAM administration showed a trend toward the expansion of human MDSC-like cells (Lineage−HLA-DR−CD11b+CD33+) with increased arginase 1 mRNA expression. Thus, CAM promoted the expansion of a unique population of immunosuppressive CD11b+Gr-1+cells essential for the immunomodulatory properties of macrolides.

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Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure

Kamo, Takehiro, Akazawa, Hiroshi, Suda, Wataru, Saga-Kamo, Akiko, Shimizu, Yu, Yagi, Hiroki, Liu, Qing, Nomura, Seitaro, Naito, Atsuhiko T., Takeda, Norifumi, Harada, Mutsuo, Toko, Haruhiro, Kumagai, Hidetoshi, Ikeda, Yuichi, Takimoto, Eiki, Suzuki, Jun-ichi, Honda, Kenya, Morita, Hidetoshi, Hattori, Masahira, Komuro, Issei

PLOS ONE 12 （ 3 ）  2017年03月

研究論文（学術雑誌）,  ISSN  1932-6203

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Microbiota Diumal Rhythmicity Programs Host Transcriptome Oscillations

Thaiss, Christoph A., Levy, Maayan, Korem, Tal, Dohnalova, Lenka, Shapiro, Hagit, Jaitin, Diego A., David, Eyal, Winter, Deborah R., Gury-BenAri, Meital, Tatirovsky, Evgeny, Tuganbaev, Timur, Federici, Sara, Zmora, Niv, Zeevi, David, Dori-Bachash, Mally, Pevsner-Fischer, Meirav, Kartvelishvily, Elena, Brandis, Alexander, Harmelin, Alon, Shibolet, Oren, Halpern, Zamir, Honda, Kenya, Amit, Ido, Segal, Eran, Elinav, Eran

CELL 167 （ 6 ） 1495 - + 2016年12月

研究論文（学術雑誌）,  ISSN  0092-8674

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Fecal microbiota transplantation for patients with steroid-resistant acute graft-versus-host disease of the gut

Kakihana, Kazuhiko, Fujioka, Yuki, Suda, Wataru, Najima, Yuho, Kuwata, Go, Sasajima, Satoshi, Mimura, Iyo, Morita, Hidetoshi, Sugiyama, Daisuke, Nishikawa, Hiroyoshi, Hattori, Masahira, Hino, Yutaro, Ikegawa, Shuntaro, Yamamoto, Keita, Toya, Takashi, Doki, Noriko, Koizumi, Koichi, Honda, Kenya, Ohashi, Kazuteru

BLOOD 128 （ 16 ） 2083 - 2088 2016年10月

研究論文（学術雑誌）,  ISSN  0006-4971

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A subpopulation of high IL-21-producing CD4(+) T cells in Peyer's Patches is induced by the microbiota and regulates germinal centers (vol 6, 30784, 2016)

Jones, Leigh, Ho, Wen Qi, Ying, Sze, Ramakrishna, Lakshmi, Srinivasan, Kandhadayar G., Yurieva, Marina, Ng, Wan Pei, Subramaniam, Sharrada, Hamadee, Nur H., Joseph, Sabrina, Dolpady, Jayashree, Atarashi, Koji, Honda, Kenya, Zolezzi, Francesca, Poidinger, Michael, Lafaille, Juan J., de Lafaille, Maria A. Curotto

SCIENTIFIC REPORTS 6 2016年10月

研究論文（学術雑誌）,  ISSN  2045-2322

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The microbiota in adaptive immune homeostasis and disease

Honda, Kenya, Littman, Dan R.

NATURE 535 （ 7610 ） 75 - 84 2016年07月

研究論文（学術雑誌）,  ISSN  0028-0836

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Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers

Saito, Takuro, Nishikawa, Hiroyoshi, Wada, Hisashi, Nagano, Yuji, Sugiyama, Daisuke, Atarashi, Koji, Maeda, Yuka, Hamaguchi, Masahide, Ohkura, Naganari, Sato, Eiichi, Nagase, Hirotsugu, Nishimura, Junichi, Yamamoto, Hirofumi, Takiguchi, Shuji, Tanoue, Takeshi, Suda, Wataru, Morita, Hidetoshi, Hattori, Masahira, Honda, Kenya, Mori, Masaki, Doki, Yuichiro, Sakaguchi, Shimon

NATURE MEDICINE 22 （ 6 ） 679 - + 2016年06月

研究論文（学術雑誌）,  ISSN  1078-8956

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Diet-dependent, microbiota-independent regulation of IL-10-producing lamina propria macrophages in the small intestine

Ochi, Takanori, Feng, Yongjia, Kitamoto, Sho, Nagao-Kitamoto, Hiroko, Kuffa, Peter, Atarashi, Koji, Honda, Kenya, Teitelbaum, Daniel H., Kamada, Nobuhiko

SCIENTIFIC REPORTS 6   75 - 84 2016年06月

研究論文（学術雑誌）,  ISSN  2045-2322

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Germinal responses in murine Peyer's Patches are regulated by a subpopulation of microbiota-induced IL-21(high) Tfh cells

Jones, Leigh A., Ho, Wen Qi, Ying, Sze, Ramakrishna, Lakshmi, Srinivasan, Kandhadayar G., Yurieva, Marina, Ng, Wan Pei, Subramaniam, Sharrada, Hamadee, Nur H., Joseph, Sabrina, Dolpady, Jayashree, Atarashi, Koji, Honda, Kenya, Zolezzi, Francesca, Poidinger, Michael, Lafaille, Juan J., de Lafaille, Maria A. Curotto

JOURNAL OF IMMUNOLOGY 196 2016年05月

研究論文（学術雑誌）,  ISSN  0022-1767

Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease

Mathewson, Nathan D., Jenq, Robert, Mathew, Anna V., Koenigsknecht, Mark, Hanash, Alan, Toubai, Tomomi, Oravecz-Wilson, Katherine, Wu, Shin-Rong, Sun, Yaping, Rossi, Corinne, Fujiwara, Hideaki, Byun, Jaeman, Shono, Yusuke, Lindemans, Caroline, Calafiore, Marco, Schmidt, Thomas C., Honda, Kenya, Young, Vincent B., Pennathur, Subramaniam, van den Brink, Marcel, Reddy, Pavan

NATURE IMMUNOLOGY 17 （ 5 ） 505 - + 2016年05月

研究論文（学術雑誌）,  ISSN  1529-2908

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Helminth infection promotes colonization resistance via type 2 immunity

Ramanan, Deepshika, Bowcutt, Rowann, Lee, Soo Ching, Tang, Mei San, Kurtz, Zachary D., Ding, Yi,Honda, Kenya, Gause, William C., Blaser, Martin J., Bonneau, Richard A., Lim, Yvonne A. L., Loke, P'ng,

SCIENCE 352 （ 6285 ） 608 - 612 2016年04月

研究論文（学術雑誌）,  ISSN  0036-8075

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Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells

Atarashi K, Tanoue T, Ando M, Kamada N, Nagano Y, Narushima S, Suda W, Imaoka A, Setoyama H, Nagamori T, Ishikawa E, Shima T, Hara T, Kado S, Jinnohara T, Ohno H, Kondo T, Toyooka K, Watanabe E, Yokoyama S, Tokoro S, Mori H, Noguchi Y, Morita H, Ivanov II, Sugiyama T, Nuñez G, Camp JG, Hattori M, Umesaki* Y, Honda K*( *corresponding authors)

CELL 163 （ 2 ） 367 - 380 2015年10月

研究論文（学術雑誌）, 共著

Microbiota-Dependent Activation of an Autoreactive T Cell Receptor Provokes Autoimmunity in an Immunologically Privileged Site.

Horai R, Zárate-Bladés CR, Dillenburg-Pilla P, Chen J, Kielczewski JL, Silver PB, Jittayasothorn Y, Chan CC, Yamane H, Honda K, Caspi RR.

IMMUNITY 43 （ 2 ） 343 - 353 2015年08月

研究論文（学術雑誌）