腸内細菌叢の網羅的解析による統合失調症の病態解明

• Project/Area Number: 18K07601
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Okayama University
• Principal Investigator: 岡久 祐子 岡山大学, 大学病院, 助教 (90583097)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Granted (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 統合失調症 / 腸内細菌叢 / メタゲノム / 次世代シーケンサー

Outline of Annual Research Achievements

統合失調症の病態に免疫学的な機序が関わることがこれまでの遺伝子解析や疫学研究で示唆されている。脳腸間の情報伝達において重要な役割を担っている腸内細菌叢は、宿主免疫系を制御することで様々な生理機能や病態形成に関わっている。これまでの研究で、腸内細菌叢は脳の発達や機能に関与することが示唆さ
れ、宿主の行動特性に変化をもたらすこと、宿主のストレスで変化することが示され、統合失調症の病態に腸内細菌叢が関与している可能性が推測される。近年の次世代シーケンサーの発達により腸内細菌叢の詳細な解析が可能になっており、本研究では、日本人統合失調症患者を対象として、次世代シーケンサーによる
腸内細菌叢の詳細な解析を行い、統合失調症の病態解明の手掛かりを得ることを目的とする。
解析の対象は、岡山大学病院精神科神経科を受診した外来または入院患者で、DSM-5及ICD-10を用いて統合失調症と診断された18歳～65歳までの患者と年齢、性を一致させた健常対照者で、研究の趣旨を説明し同意の得られた対象者から糞便採取を行う。統合失調症患者の臨床症状や重症度、認知機能との関連も検討する。検討に用いる評価尺度である陽性・陰性症状評価尺度(PANSS)、全般的機能評価尺度(GAF)、臨床的全般改善度(CGI)、統合失調症認知機能簡易評価尺度
(BACS)、Wisconsin Card Sorted Test、前頭葉機能検査(FAB)、Japanese Adult Reading Test 、Wecheler Adult Intelligence Scale -Reviced (WAIS-R)等を統合失調症患者に施行した。

Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

解析方法の検討を新たに行い対象となる統合失調症患者の診察、臨床評価、試料採取を行っているが、COVID-19対策のため、試料の採取が中断している状態である。事態が収束するのを待ち、解析必要数が揃い次第解析を行う予定としている。

Strategy for Future Research Activity

岡山大学病院精神科神経科を受診した外来または入院患者で、DSM-5及びICD-10を用いて統合失調症と診断された18歳～65歳までの患者と年齢、性を一致させた健常対照者で、研究の趣旨を説明し同意の得られた対象者から糞便採取を行う。糞便は採取後すぐに－80℃で凍結保存したのち溶菌操作により細菌叢DNAを抽出する。次年度中には統合失調症患者50サンプル、健常対照群50サンプルを対象にメタゲノム解析を行い、統合失調症患者と健常対照者での腸内細菌叢の相違点を同定する。
次の解析として、腸内細菌叢に影響を及ぼす様々な要因と腸内細菌叢の関連についての検討も行う。

Research Products

• [Journal Article] Mechanisms Underlying the Comorbidity of Schizophrenia and Type 2 Diabetes Mellitus (2021)
  • Author(s): Mizuki Yutaka、Sakamoto Shinji、Okahisa Yuko、Yada Yuji、Hashimoto Nozomu、Takaki Manabu、Yamada Norihito
  • Journal Title: Int J Neuropsychopharmacol . Volume: in press Pages: 000-000
  • DOI: 10.1093/ijnp/pyaa097
  • NAID: 120007045004
  • Peer Reviewed / Open Access
• [Journal Article] The relationship between plasma clozapine concentration and clinical outcome: a cross-sectional study. (2021)
  • Author(s): Yada Y, Kitagawa K, Sakamoto S, Ozawa A, Nakada A, Kashiwagi H, Okahisa Y, Takao S, Takaki M, Kishi Y, Yamada N.
  • Journal Title: Acta Psychiatr Scand . Volume: 143 Pages: 227-237
  • DOI: 10.1111/acps.13264
  • Peer Reviewed / Open Access
• [Journal Article] Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia (2020)
  • Author(s): Ishizuka Kanako、Yoshida Tomoyuki、Kawabata Takeshi、Imai Ayako、Mori Hisashi、Kimura Hiroki、Inada Toshiya、Okahisa Yuko、Egawa Jun、Usami Masahide、Kushima Itaru、Morikawa Mako、Okada Takashi、Ikeda Masashi、Branko Aleksic、Mori Daisuke、Someya Toshiyuki、Iwata Nakao、Ozaki Norio
  • Journal Title: Journal of Neurodevelopmental Disorders Volume: 12 Pages: 25-25
  • DOI: 10.1186/s11689-020-09325-2
  • Peer Reviewed / Open Access
• [Journal Article] Rare single-nucleotide DAB1 variants and their contribution to Schizophrenia and autism spectrum disorder susceptibility (2020)
  • Author(s): Nawa Yoshihiro、Kimura Hiroki、Mori Daisuke、Kato Hidekazu、Toyama Miho、Furuta Sho、Yu Yanjie、Ishizuka Kanako、Kushima Itaru、Aleksic Branko、Arioka Yuko、Morikawa Mako、Okada Takashi、Inada Toshiya、Kaibuchi Kozo、Ikeda Masashi、Iwata Nakao、Suzuki Michio、Okahisa Yuko、Egawa Jun et al
  • Journal Title: Human Genome Variation Volume: 7 Pages: 37-37
  • DOI: 10.1038/s41439-020-00125-7
  • Peer Reviewed / Open Access
• [Journal Article] Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder. (2020)
  • Author(s): Kato H, Kushima I, Mori D, Yoshimi A, Aleksic B, Nawa Y, et al.
  • Journal Title: Transl Psychiatry. Volume: 10 Pages: 421-421
  • DOI: 10.1038/s41398-020-01107-7
  • Peer Reviewed / Open Access
• [Journal Article] Switching strategies for antipsychotic monotherapy in schizophrenia: a multi-center cohort study of aripiprazole (2020)
  • Author(s): Obayashi Y, Mitsui S, Sakamoto S, Minao N, Yoshimura B, Kono T, Yada Y, Okahisa Y, Takao S, Kishi Y, Takeda T, Takaki M, Yamada N.
  • Journal Title: Psychopharmacology Volume: 237(1) Pages: 167-175
  • DOI: 10.1007/s00213-019-05352-7
  • Peer Reviewed
• [Journal Article] Anti-NMDA-receptor antibody in initial diagnosis of mood disorder. (2020)
  • Author(s): Kawai H, Takaki M, Sakamoto S, Shibata T, Tsuchida A, Yoshimura B, Yada Y, Matsumoto N, Sato K, Abe K, Okahisa Y, Kishi Y, Takao S, Tsutsui K, Kanbayashi T, Tanaka K, Yamada N.
  • Journal Title: Neuropsychiatr Dis Treat Volume: 29(9) Pages: 1041-1050
  • DOI: 10.1016/j.euroneuro.2019.07.137
  • Peer Reviewed
• [Journal Article] Anti-N-Methyl-D-Aspartate Receptor Encephalitis in Psychiatry (2019)
  • Author(s): Sakamoto S, Kawai H, Okahisa Y, Tsutsui K, Kanbayashi T, Tanaka K, Mizuki Y, Takaki M, Yamada N.
  • Journal Title: Acta Medica Okayama Volume: 73 Issue: 3 Pages: 189-195
  • DOI: 10.18926/AMO/56860
  • NAID: 120006647996
  • URL: http://ousar.lib.okayama-u.ac.jp/56860
  • Peer Reviewed / Open Access
• [Journal Article] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect (2019)
  • Author(s): Ikeda M,Takahashi A,Kamatani Y,Momozawa Y,Saito T,Kondo K,Shimasaki A,Kawase K,Sakusabe T,Iwayama Y,Toyota T,Wakuda T,Kikuchi M,Kanahara N,Yamamori H,Yasuda Y,Watanabe Y,Hoya S,Aleksic B,Kushima I,Arai H,Takaki M,Hattori K,Kunugi H,Okahisa Y,Ohnuma T,Ozaki N,Someya T,Hashimoto R,Yoshikawa T,Kubo M,Iwata N
  • Journal Title: Schizophr Bull Volume: 印刷中 Pages: 824-834
  • DOI: 10.1093/schbul/sby140
  • Peer Reviewed / Open Access
• [Journal Article] A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder. (2018)
  • Author(s): Ikeda M, Shimasaki A, Takahashi A,et al.
  • Journal Title: Mol Psychiatry. Volume: in press Pages: 639-647
  • DOI: 10.1038/mp.2016.259
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Rare loss of function mutations in N-methyl-d-aspartate glutamate receptors and their contributions to schizophrenia susceptibility (2018)
  • Author(s): Yu Yanjie、Lin Yingni、Takasaki Yuto、Wang Chenyao、Kimura Hiroki、Xing Jingrui、Ishizuka Kanako、Toyama Miho、Kushima Itaru、Mori Daisuke、Arioka Yuko、Uno Yota、Shiino Tomoko、Nakamura Yukako、Okada Takashi、Morikawa Mako、Ikeda Masashi、Iwata Nakao、Okahisa Yuko、Takaki Manabu、Sakamoto Shinji、et al.
  • Journal Title: Transl Psychiatry Volume: 8 Pages: 12-12
  • DOI: 10.1038/s41398-017-0061-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Assessment of a glyoxalase I frameshift variant, p.P122fs, in Japanese patients with schizophrenia. (2018)
  • Author(s): Ishizuka K, Kimura H, Kushima I, Inada T, Okahisa Y, Ikeda M, Iwata N, Mori D, Aleksic B, Ozaki N.
  • Journal Title: Psychiatr Genet Volume: 5 Pages: 90-93
  • DOI: 10.1097/ypg.0000000000000204
  • Peer Reviewed / Open Access
• [Journal Article] Effects of the antipsychotics haloperidol, clozapine, and aripiprazole on the dendritic spine. (2018)
  • Author(s): Takaki M, Kodama M, Mizuki Y, Kawai H, Yoshimura B, Kishimoto M, Sakamoto S, Okahisa Y, Yamada N.
  • Journal Title: Eur Neuropsychopharmacol. Volume: 28(5) Pages: 610-619
  • DOI: 10.1016/j.euroneuro.2018.03.004
  • Peer Reviewed / Open Access
• [Presentation] The relationship of N-methyl-D-aspartate receptor antibody and psychiatric disorders (2018)
  • Author(s): Kawai H, Sakamoto S, Kishimoto M, Okahisa Y, Takaki M, Yamada N.
  • Organizer: CINP 31st World Congress
  • Int'l Joint Research
• [Presentation] Effects of the antipsychotics haloperidol, clozapine, and aripiprazole on the dendritic spine (2018)
  • Author(s): Takaki M, Kodama M, Mizuki Y, Kawai H, Yoshimura B, Kishimoto M, Sakamoto S, Okahisa Y, Yamada N.
  • Organizer: CINP 31st World Congress
  • Int'l Joint Research