Takeshita, Kozue

写真a

Affiliation

School of Medicine, Department of Microbiology and Immunology （Shinanomachi）

Position

Senior Assistant Professor (Non-tenured)/Assistant Professor (Non-tenured)
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Academic Degrees 【 Display / hide 】

  • 医学博士, 慶応義塾大学医学部大学院

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Papers 【 Display / hide 】

  • An old model with new insights: endogenous retroviruses drive the evolvement toward ASD susceptibility and hijack transcription machinery during development

    Lin C.W., Ellegood J., Tamada K., Miura I., Konda M., Takeshita K., Atarashi K., Lerch J.P., Wakana S., McHugh T.J., Takumi T.

    Molecular Psychiatry （Molecular Psychiatry)   2023

    ISSN  13594184

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    The BTBR T+Itpr3tf/J (BTBR/J) strain is one of the most valid models of idiopathic autism, serving as a potent forward genetics tool to dissect the complexity of autism. We found that a sister strain with an intact corpus callosum, BTBR TF/ArtRbrc (BTBR/R), showed more prominent autism core symptoms but moderate ultrasonic communication/normal hippocampus-dependent memory, which may mimic autism in the high functioning spectrum. Intriguingly, disturbed epigenetic silencing mechanism leads to hyperactive endogenous retrovirus (ERV), a mobile genetic element of ancient retroviral infection, which increases de novo copy number variation (CNV) formation in the two BTBR strains. This feature makes the BTBR strain a still evolving multiple-loci model toward higher ASD susceptibility. Furthermore, active ERV, analogous to virus infection, evades the integrated stress response (ISR) of host defense and hijacks the transcriptional machinery during embryonic development in the BTBR strains. These results suggest dual roles of ERV in the pathogenesis of ASD, driving host genome evolution at a long-term scale and managing cellular pathways in response to viral infection, which has immediate effects on embryonic development. The wild-type Draxin expression in BTBR/R also makes this substrain a more precise model to investigate the core etiology of autism without the interference of impaired forebrain bundles as in BTBR/J.

  • Identification of trypsin-degrading commensals in the large intestine.

    Youxian Li, Eiichiro Watanabe, Yusuke Kawashima, Damian R Plichta, Zhujun Wang, Makoto Ujike, Qi Yan Ang, Runrun Wu, Munehiro Furuichi, Kozue Takeshita, Koji Yoshida, Keita Nishiyama, Sean M Kearney, Wataru Suda, Masahira Hattori, Satoshi Sasajima, Takahiro Matsunaga, Xiaoxi Zhang, Kazuto Watanabe, Jun Fujishiro, Jason M Norman, Bernat Olle, Shutoku Matsuyama, Ho Namkoong, Yoshifumi Uwamino, Makoto Ishii, Koichi Fukunaga, Naoki Hasegawa, Osamu Ohara, Ramnik J Xavier, Koji Atarashi, Kenya Honda

    Nature （Nature)  609 （ 7927 ） 582 - 589 2022.09

    ISSN  00280836

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    Increased levels of proteases, such as trypsin, in the distal intestine have been implicated in intestinal pathological conditions1-3. However, the players and mechanisms that underlie protease regulation in the intestinal lumen have remained unclear. Here we show that Paraprevotella strains isolated from the faecal microbiome of healthy human donors are potent trypsin-degrading commensals. Mechanistically, Paraprevotella recruit trypsin to the bacterial surface through type IX secretion system-dependent polysaccharide-anchoring proteins to promote trypsin autolysis. Paraprevotella colonization protects IgA from trypsin degradation and enhances the effectiveness of oral vaccines against Citrobacter rodentium. Moreover, Paraprevotella colonization inhibits lethal infection with murine hepatitis virus-2, a mouse coronavirus that is dependent on trypsin and trypsin-like proteases for entry into host cells4,5. Consistently, carriage of putative genes involved in trypsin degradation in the gut microbiome was associated with reduced severity of diarrhoea in patients with SARS-CoV-2 infection. Thus, trypsin-degrading commensal colonization may contribute to the maintenance of intestinal homeostasis and protection from pathogen infection.

  • A common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model.

    Chia-Wen Lin, Dian E Septyaningtrias, Hsu-Wen Chao, Mikiko Konda, Koji Atarashi, Kozue Takeshita, Kota Tamada, Jun Nomura, Yohei Sasagawa, Kaori Tanaka, Itoshi Nikaido, Kenya Honda, Thomas J McHugh, Toru Takumi

    Molecular psychiatry （Molecular Psychiatry)  27 （ 8 ） 3343 - 3354 2022.05

    Accepted,  ISSN  13594184

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    Immune dysregulation plays a key role in the pathogenesis of autism. Changes occurring at the systemic level, from brain inflammation to disturbed innate/adaptive immune in the periphery, are frequently observed in patients with autism; however, the intrinsic mechanisms behind them remain elusive. We hypothesize a common etiology may lie in progenitors of different types underlying widespread immune dysregulation. By single-cell RNA sequencing (sc-RNA seq), we trace the developmental origins of immune dysregulation in a mouse model of idiopathic autism. It is found that both in aorta-gonad-mesonephros (AGM) and yolk sac (YS) progenitors, the dysregulation of HDAC1-mediated epigenetic machinery alters definitive hematopoiesis during embryogenesis and downregulates the expression of the AP-1 complex for microglia development. Subsequently, these changes result in the dysregulation of the immune system, leading to gut dysbiosis and hyperactive microglia in the brain. We further confirm that dysregulated immune profiles are associated with specific microbiota composition, which may serve as a biomarker to identify autism of immune-dysregulated subtypes. Our findings elucidate a shared mechanism for the origin of immune dysregulation from the brain to the gut in autism and provide new insight to dissecting the heterogeneity of autism, as well as the therapeutic potential of targeting immune-dysregulated autism subtypes.

  • Hematopoietic Cell Transplantation Rescues Inflammatory Bowel Disease and Dysbiosis of Gut Microbiota in XIAP Deficiency.

    Shintaro Ono, Kozue Takeshita, Yuko Kiridoshi, Motohiro Kato, Takahiro Kamiya, Akihiro Hoshino, Masakatsu Yanagimachi, Katsuhiro Arai, Ichiro Takeuchi, Nariaki Toita, Toshihiko Imamura, Yoji Sasahara, Junichi Sugita, Kazuko Hamamoto, Masanobu Takeuchi, Shoji Saito, Masaei Onuma, Hiroshi Tsujimoto, Masahiro Yasui, Takashi Taga, Yuki Arakawa, Yuichi Mitani, Nobuyuki Yamamoto, Kohsuke Imai, Wataru Suda, Masahira Hattori, Osamu Ohara, Tomohiro Morio, Kenya Honda, Hirokazu Kanegane

    The journal of allergy and clinical immunology. In practice （Journal of Allergy and Clinical Immunology: In Practice)  9 （ 10 ） 3767 - 3780 2021.10

    ISSN  22132198

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    BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment. OBJECTIVE: To study (1) the effect of HCT on patients with XIAP deficiency undergoing HCT, (2) the status of XIAP deficiency-associated IBD after HCT, and (3) the gut microbiota of XIAP deficiency-associated IBD before and after HCT. METHODS: A nationwide survey of patients with XIAP deficiency was conducted. A spreadsheet questionnaire was collected from the physicians. Feces samples collected from the patients before and after HCT and their healthy family members were analyzed. RESULTS: Twenty-six patients with XIAP deficiency underwent HCT by the end of March 2020, and 22 patients (84.6%) survived. All the survivors underwent a fludarabine-based reduced-intensity condition regimen. Acute graft-versus-host disease was observed in 17 patients (65.4%). Nineteen patients experienced refractory IBD before undergoing HCT. IBD improved remarkably after HCT. After HCT, the colonoscopic and pathological symptoms were restored to normal, and the pediatric ulcerative colitis activity index improved significantly. Gut microbiota indicated dysbiosis before HCT; however, it was improved to resemble that of the healthy family members after HCT. CONCLUSIONS: This study revealed that HCT has a favorable outcome for XIAP deficiency. HCT rescues gut inflammation and dysbiosis in patients with XIAP deficiency.

  • Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians.

    Yuko Sato, Koji Atarashi, Damian R Plichta, Yasumichi Arai, Satoshi Sasajima, Sean M Kearney, Wataru Suda, Kozue Takeshita, Takahiro Sasaki, Shoki Okamoto, Ashwin N Skelly, Yuki Okamura, Hera Vlamakis, Youxian Li, Takeshi Tanoue, Hajime Takei, Hiroshi Nittono, Seiko Narushima, Junichiro Irie, Hiroshi Itoh, Kyoji Moriya, Yuki Sugiura, Makoto Suematsu, Nobuko Moritoki, Shinsuke Shibata, Dan R Littman, Michael A Fischbach, Yoshifumi Uwamino, Takashi Inoue, Akira Honda, Masahira Hattori, Tsuyoshi Murai, Ramnik J Xavier, Nobuyoshi Hirose, Kenya Honda

    Nature （Nature)  599 （ 7885 ） 458 - 464 2021.07

    ISSN  00280836

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    Centenarians have a decreased susceptibility to ageing-associated illnesses, chronic inflammation and infectious diseases1-3. Here we show that centenarians have a distinct gut microbiome that is enriched in microorganisms that are capable of generating unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from the faecal microbiota of a centenarian, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3β-HSDH) were responsible for the production of isoalloLCA. IsoalloLCA exerted potent antimicrobial effects against Gram-positive (but not Gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of infection with pathobionts, thereby potentially contributing to the maintenance of intestinal homeostasis.

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Reviews, Commentaries, etc. 【 Display / hide 】

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Courses Taught 【 Display / hide 】

  • MICROBIOLOGY

    2023

  • MICROBIOLOGY

    2022

  • MICROBIOLOGY

    2021

  • MICROBIOLOGY

    2020

  • MICROBIOLOGY

    2019

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