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Gut microbiome- as a potential target for prevention of PCOS development-

Research Project

Project/Area Number 19K09749
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56040:Obstetrics and gynecology-related
Research InstitutionThe University of Tokyo

Principal Investigator

Harada Miyuki  東京大学, 医学部附属病院, 准教授 (70451812)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords多嚢胞性卵巣症候群 / 不妊症 / 腸内細菌叢 / プレコンセプションケア / 胎内環境 / 卵巣 / アンドロゲン
Outline of Research at the Start

多嚢胞性卵巣症候群(PCOS)は、主として青年期(15歳頃~)に発症し、排卵障害の原因となり、また妊娠成立後も周産期合併症の発症頻度が高く、胎児への影響も懸念されている。しかしPCOSの発症機序が明らかでないため、生活指導や対症療法以外の有効な方策が打ち出せていない。本研究では、胎児期の高アンドロゲン曝露によって成長過程の腸内細菌叢形成に異常が生じ、その結果卵巣病態と代謝異常などの複合的な異常から成る病態であるPCOSが発症するという仮説を明らかにする。そしてPCOSに対して、プロバイオティクス投与による腸内細菌叢是正という、病因をターゲットとした治療さらには発症予防戦略の開発を図る。

Outline of Final Research Achievements

It has been recently recognized that prenatal androgen exposure is involved in the development of polycystic ovary syndrome (PCOS) in adulthood. In addition, the gut microbiome in adult patients and rodents with PCOS differs from that of healthy individuals. Moreover, recent studies have suggested that the gut microbiome may play a causative role in the pathogenesis of PCOS. We studied the development of PCOS-like phenotypes in prenatally androgenized (PNA) female mice and compared the gut microbiome of PNA and control offspring from 4 to 16 weeks of age. Our results showed that abnormalities in the gut microbiome appear as early as or even before PCOS-like phenotypes develop in PNA mice. Thus, the gut microbiome in early life is a potential target for the prevention of PCOS in later life.

Academic Significance and Societal Importance of the Research Achievements

PCOSは生殖年齢女性で最も罹患頻度の高い(6-20%)内分泌疾患で、排卵障害の原因となり、また妊娠成立後も周産期合併症の発症頻度が高い。したがって、PCOS女性に対しては、不妊治療成績ならびに周産期予後の向上のために、挙児努力前からの健康管理すなわちプレコンセプションケアが勧められる。本研究は、腸内細菌叢への早期介入によりPCOSを予防できる可能性を示唆しており、PCOSの予防戦略を提示したという点で画期的であり、またプレ/プロ/ポストバイオティクスによる介入は、挙児努力中さらには妊娠中の女性に対しても適用可能な介入であり、実現可能性の高い戦略である。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (32 results)

All 2022 2021 2020 2019

All Journal Article (17 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 17 results,  Open Access: 9 results) Presentation (15 results) (of which Int'l Joint Research: 5 results,  Invited: 8 results)

  • [Journal Article] The possible effects of the Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 on the practice of fertility preservation in female cancer patients in Japan2022

    • Author(s)
      Kunitomi Chisato、Harada Miyuki、Sanada Yuko、Kusamoto Akari、Takai Yasushi、Furui Tatsuro、Kitagawa Yuko、Yamada Mitsutoshi、Watanabe Chie、Tsugawa Koichiro、Nishiyama Hiroyuki、Hosoi Hajime、Miyachi Mitsuru、Sugiyama Kazuhiko、Maeda Yoshinobu、Kawai Akira、Hamatani Toshio、Fujio Keishi、Suzuki Nao、Osuga Yutaka
    • Journal Title

      Reproductive Medicine and Biology

      Volume: 21 Issue: 1

    • DOI

      10.1002/rmb2.12453

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 12022

    • Author(s)
      Harada Miyuki、Kimura Fuminori、Takai Yasushi、et al.
    • Journal Title

      International Journal of Clinical Oncology

      Volume: 27 Issue: 2 Pages: 265-280

    • DOI

      10.1007/s10147-021-02081-w

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Temporal relationship between alterations in the gut microbiome and the development of polycystic ovary syndrome‐like phenotypes in prenatally androgenized female mice2021

    • Author(s)
      Kusamoto Akari、Harada Miyuki、Azhary Jerilee M. K.、Kunitomi Chisato、Nose Emi、Koike Hiroshi、Xu Zixin、Urata Yoko、Kaku Tetsuaki、Takahashi Nozomi、Wada‐Hiraike Osamu、Hirota Yasushi、Koga Kaori、Fujii Tomoyuki、Osuga Yutaka
    • Journal Title

      The FASEB Journal

      Volume: 35 Issue: 11

    • DOI

      10.1096/fj.202101051r

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Does polycystic ovary syndrome independently affect oncologic and reproductive outcomes in patients with endometrial cancer receiving fertility-sparing treatment?2021

    • Author(s)
      Harada Miyuki、Osuga Yutaka
    • Journal Title

      Journal of Gynecologic Oncology

      Volume: 32 Issue: 5

    • DOI

      10.3802/jgo.2021.32.e80

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pregnancy outcomes in children, adolescents, and young adults that survived cancer: A nationwide survey in Japan2021

    • Author(s)
      Yasuoka Toshiaki、Iwama Noriyuki、Ota Kuniaki、Harada Miyuki、Hasegawa Junichi、Yaegashi Nobuo、Sugiyama Takashi、Suzuki Nao、Osuga Yutaka
    • Journal Title

      Journal of Obstetrics and Gynaecology Research

      Volume: 47 Issue: 9 Pages: 3352-3361

    • DOI

      10.1111/jog.14909

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Assisted reproductive technology in Japan: A summary report for 2019 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology2021

    • Author(s)
      Katagiri Yukiko、Jwa Seung Chik、Kuwahara Akira、Iwasa Takeshi、Ono Masanori、Kato Keiichi、Kishi Hiroshi、Kuwabara Yoshimitsu、Harada Miyuki、Hamatani Toshio、Osuga Yutaka
    • Journal Title

      Reproductive Medicine and Biology

      Volume: 21 Issue: 1

    • DOI

      10.1002/rmb2.12434

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Endoplasmic reticulum stress: a key regulator of the follicular microenvironment in the ovary2021

    • Author(s)
      Harada M, Takahashi N, Azhary JM, Kunitomi C, Fujii T, Osuga Y.
    • Journal Title

      Mol Hum Reprod.

      Volume: 27 Issue: 1

    • DOI

      10.1093/molehr/gaaa088

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Induction of aryl hydrocarbon receptor in granulosa cells by endoplasmic reticulum stress contributes to pathology of polycystic ovary syndrome2021

    • Author(s)
      Kunitomi C, Harada M, Kusamoto A, Azhary JM, Nose E, Koike H, Xu Z, Urata Y, Takahashi N, Wada-Hiraike O, Hirota Y, Koga K, Fujii T, Osuga Y.
    • Journal Title

      Mol Hum Reprod.

      Volume: 27 Issue: 3 Pages: 234-234

    • DOI

      10.1093/molehr/gaab003

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] National survey of primary amenorrhea and relevant conditions in Japan2021

    • Author(s)
      Haraguchi H, Harada M, Kashimada K, Horikawa R, Sakakibara H, Shozu M, Fujii T, Osuga Y, Kugu K.
    • Journal Title

      J Obstet Gynaecol Res.

      Volume: 47 Issue: 2 Pages: 774-777

    • DOI

      10.1111/jog.14606

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Fertility preservation in patients receiving gonadotoxic therapies for systemic autoimmune diseases in Japan2021

    • Author(s)
      Tsuchida Y, Harada M, Shoda H, Goto A, Suzuki N, Murashima A, Osuga Y, Fujio K.
    • Journal Title

      Mod Rheumatol.

      Volume: Jan 18 Issue: 5 Pages: 1-8

    • DOI

      10.1080/14397595.2020.1856020

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Assisted reproductive technology in Japan: A summary report for 2018 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology2020

    • Author(s)
      Ishihara O, Jwa SC, Kuwahara A, Katagiri Y, Kuwabara Y, Hamatani T, Harada M, Osuga Y.
    • Journal Title

      Reprod Med Biol.

      Volume: 20 Issue: 1 Pages: 3-12

    • DOI

      10.1002/rmb2.12358

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Androgens Increase Accumulation of Advanced Glycation End Products in Granulosa Cells by Activating ER Stress in PCOS2020

    • Author(s)
      Azhary Jerilee M K、Harada Miyuki、Kunitomi Chisato、Kusamoto Akari、Takahashi Nozomi、Nose Emi、Oi Nagisa、Wada-Hiraike Osamu、Urata Yoko、Hirata Tetsuya、Hirota Yasushi、Koga Kaori、Fujii Tomoyuki、Osuga Yutaka
    • Journal Title

      Endocrinology

      Volume: 161 Issue: 2 Pages: 1-13

    • DOI

      10.1210/endocr/bqaa015

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Preclinical validation of the new vitrification device possessing a feature of absorbing excess vitrification solution for the cryopreservation of human embryos2020

    • Author(s)
      Takahashi Nozomi、Harada Miyuki、Oi Nagisa、Izumi Gentaro、Momozawa Kenji、Matsuzawa Atsushi、Tokunaga Yukio、Hirata Tetsuya、Fujii Tomoyuki、Osuga Yutaka
    • Journal Title

      Journal of Obstetrics and Gynaecology Research

      Volume: 46 Issue: 2 Pages: 302-309

    • DOI

      10.1111/jog.14176

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Activation of endoplasmic reticulum stress mediates oxidative stress?induced apoptosis of granulosa cells in ovaries affected by endometrioma2019

    • Author(s)
      Kunitomi Chisato、Harada Miyuki、Takahashi Nozomi、Azhary Jerilee M K、Kusamoto Akari、Nose Emi、Oi Nagisa、Takeuchi Arisa、Wada-Hiraike Osamu、Hirata Tetsuya、Hirota Yasushi、Koga Kaori、Fujii Tomoyuki、Osuga Yutaka
    • Journal Title

      Molecular Human Reproduction

      Volume: 26 Issue: 1 Pages: 40-52

    • DOI

      10.1093/molehr/gaz066

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Accumulation of advanced glycation end products in follicles is associated with poor oocyte developmental competence2019

    • Author(s)
      Takahashi Nozomi、Harada Miyuki、Azhary Jerilee M K、Kunitomi Chisato、Nose Emi、Terao Hiromi、Koike Hiroshi、Wada-Hiraike Osamu、Hirata Tetsuya、Hirota Yasushi、Koga Kaori、Fujii Tomoyuki、Osuga Yutaka
    • Journal Title

      Molecular Human Reproduction

      Volume: 25 Issue: 11 Pages: 684-694

    • DOI

      10.1093/molehr/gaz050

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of oxidative stress in follicular fluid on embryos of patients undergoing assisted reproductive technology treatment2019

    • Author(s)
      Terao Hiromi、Wada‐Hiraike Osamu、Nagumo Aiko、Kunitomi Chisato、Azhary Jerilee M. K.、Harada Miyuki、Hirata Tetsuya、Hirota Yasushi、Koga Kaori、Fujii Tomoyuki、Osuga Yutaka
    • Journal Title

      Journal of Obstetrics and Gynaecology Research

      Volume: 45 Issue: 9 Pages: 1884-1891

    • DOI

      10.1111/jog.14040

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Endometriosis Triggers Excessive Activation of Primordial Follicles via PI3K-PTEN-Akt-Foxo3 Pathway2019

    • Author(s)
      Takeuchi Arisa、Koga Kaori、Satake Erina、Makabe Tomoko、Taguchi Ayumi、Miyashita Mariko、Takamura Masashi、Harada Miyuki、Hirata Tetsuya、Hirota Yasushi、Yoshino Osamu、Wada-Hiraike Osamu、Fujii Tomoyuki、Osuga Yutaka
    • Journal Title

      The Journal of Clinical Endocrinology & Metabolism

      Volume: 104 Issue: 11 Pages: 5547-5554

    • DOI

      10.1210/jc.2019-00281

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Lecture 5. Oncofertility in Japan -Past, present, and future-2022

    • Author(s)
      Miyuki Harada
    • Organizer
      1st Asian-Oceania Society Pediatric Adolescent Gynaecology (AOSPAG) meeting
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 生涯研修プログラム10 多嚢胞性卵巣症候群 up-to-date 「PCOSの病態」2021

    • Author(s)
      原田美由紀
    • Organizer
      第73回日本産科婦人科学会学術講演会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 基調講演 「医学的適応による妊孕性温存治療の現況と展望」2021

    • Author(s)
      原田美由紀
    • Organizer
      第155回生殖医学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 教育講演4 「多嚢胞性卵巣症候群(PCOS)―古くて新しい疾患の現在地とこれから―」2021

    • Author(s)
      原田美由紀
    • Organizer
      第66回日本生殖医療学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 胎内高アンドロゲン曝露により作成される多嚢胞性卵巣症候群(PCOS)マウスモデルの成長過程における表現型と腸内細菌叢の経時的変化の解析2021

    • Author(s)
      草本朱里、原田美由紀、國富千智、小池洋 田中つるぎ、賀来哲明、平池修、藤井知行、大須賀穣
    • Organizer
      第66回日本生殖医療学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Examination of temporal changes in phenotype and gut microbiome during the process of growth in polycystic ovary syndrome (PCOS) model induced by prenatal androgen exposure2021

    • Author(s)
      Akari Kusamoto, Miyuki Harada, Jerilee MK Azhary, Chisato Kunitomi, Emi Nose, Hiroshi Koike, Zixin Xu, Yoko Urata, Nozomi Takahashi, Yutaka Osuga
    • Organizer
      37th ESHRE
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Endoplasmic reticulum (ER) stress-induced aryl hydrocarbon receptor (AhR) in granulosa cells contributes to the pathophysiology of PCOS2021

    • Author(s)
      Kunitomi C, Harada M, Kusamoto A, Fujii T, Osuga Y
    • Organizer
      102nd ENDO
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Androgens increase accumulation of advanced glycation end products (AGEs) in granulosa cells by activating endoplasmic reticulum (ER) stress in polycystic ovary syndrome (PCOS) (Oral presentation)2020

    • Author(s)
      Harada M, Azhary JMK, Kunitomi C, Kusamoto A, Takahashi N, Nose E, Oi N, Wada-Hiraike O, Urata Y, Fujii T, Osuga Y
    • Organizer
      36th ESHRE
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] 第11回ロート女性健康科学研究賞 受賞記念講演 「卵巣局所環境に着目した卵巣機能制御機構の解明と今後の展望」2020

    • Author(s)
      原田美由紀
    • Organizer
      第72回日本産科婦人科学会学術講演会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 女性医師専門医育成再教育委員会企画 JES We Can: これから子供をもつ若年男女の健康・妊孕性とepigenesisから次世代の健康を考える 「卵巣機能から考えるプレコンセプションケア」2020

    • Author(s)
      原田美由紀
    • Organizer
      第93回日本内分泌学会学術総会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] シンポジウム:卵巣における内分泌学「卵巣における小胞体ストレスの役割」2020

    • Author(s)
      原田美由紀
    • Organizer
      第93回日本内分泌学会学術総会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 終末糖化産物(AGEs)の卵胞内への蓄積は卵子の発生能低下と関連する2020

    • Author(s)
      原田美由紀、高橋望、國富千智、草本朱里、小池洋、平池修、藤井知行、大須賀穣
    • Organizer
      第20回抗加齢医学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Accumulation of advanced glycation end products in follicles is associated with poor oocyte quality: inducing inflammation in granulosa cells via activation of unfolded protein response2019

    • Author(s)
      Miyuki Harada, Nozomi Takahashi, Jerilee MK Azhary, Chisato Kunitomi, Emi Nose, Hiromi Terao, Osamu Wada-Hiraike, Yasushi Hirota, Tomoyuki Fujii, Yutaka Osuga
    • Organizer
      35th ESHRE
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] シンポジウム 2 妊孕性改善と生児獲得を目指したpreconception care 「妊孕性改善を目的とした卵巣小胞体ストレス機構の解明と治療戦略の開発」2019

    • Author(s)
      原田美由紀
    • Organizer
      第71回日本産科婦人科学会学術講演会
    • Related Report
      2019 Research-status Report
  • [Presentation] シンポジウム6 臓器横断的に考える肥満症の健康障害: 領域横断的肥満症WG連携企画②「肥満と女性の生殖機能」2019

    • Author(s)
      原田美由紀
    • Organizer
      第40回日本肥満学会/第37回日本肥満症治療学会
    • Related Report
      2019 Research-status Report
    • Invited

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Published: 2019-04-18   Modified: 2023-01-30  

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