A metagenomic approach to unveil the association between gut microbiota and molecular pathophysiology of schizophrenia

• 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, 講師 (90583097)
• Project Period (FY): 2018-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• 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、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、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した。
解析の対象は、精神科病院に入院中の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MGキット（Nomaguchi et al. 2023）を用いて採便した。続いて、得られた糞便を16S rRNA菌叢解析により腸内細菌の種類や構成を網羅的に解析した。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ため、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)を統合失調症患者に施行した。
統合失調症患者30名と健常対照者30名で解析を行ったが、腸内細菌叢に大きな違いは見られなかった。今後、代謝物質の解析等、多方面からの検討を継続する予定である。

Research Products

• [Journal Article] Comparison between olanzapine and aripiprazole treatment for 104?weeks after hospital discharge in schizophrenia spectrum disorders: a multicenter retrospective cohort study in a real-world setting (2023)
  • Author(s): Hosokawa T, Miyaji C, Yoshimura Y, Washida K, Yada Y,Sakamoto S, Okahisa Y, Takao S, Nomura A, Kishi Y, Harada T, Takaki M, Takeda T, Yamada N
  • Journal Title: Psychopharmacology Volume: 240(9) Issue: 9 Pages: 1911-1920
  • DOI: 10.1007/s00213-023-06407-6
  • Peer Reviewed / Open Access
• [Journal Article] Initial Outcomes of the Safe and Sound Protocol on Patients with Adult Autism Spectrum Disorder: Exploratory Pilot Study. (2023)
  • Author(s): Kawai H, Kishimoto M, Okahisa Y, Sakamoto S, Terada S, Takaki M
  • Journal Title: International journal of environmental research and public health Volume: 20(6) Issue: 6 Pages: 4862-4862
  • DOI: 10.3390/ijerph20064862
  • Peer Reviewed / Open Access
• [Journal Article] The validity of atypical psychosis diagnostic criteria to detect anti-NMDA receptor encephalitis with psychiatric symptoms (2022)
  • Author(s): Hinotsu K, Miyaji C, Yada Y, Kawai H, Sakamoto S, Okahisa Y, Tsutsui K, Kanbayashi T, Tanaka K, Takao S, Kishi Y, Takaki M, Yamada N.
  • Journal Title: Schizophr Res . Volume: 248 Pages: 292-299
  • DOI: 10.1016/j.schres.2022.08.024
  • Peer Reviewed
• [Journal Article] Transdiagnostic comparisons of intellectual abilities and work outcome in patients with mental disorders: multicentre study (2022)
  • Author(s): Sumiyoshi C, Ohi K, Fujino H, Yamamori H, Fujimoto M, Yasuda Y, Uno Y, Takahashi J, Morita K, Katsuki A, Yamamoto M, Okahisa Y, Sata A, Katsumoto E, Koeda M, Hirano Y, Nakataki M, Matsumoto J, Miura K, Hashimoto N, Makinodan M, Takahashi T, Nemoto K, Kishimoto T, Suzuki M, Sumiyoshi T, Hashimoto R.
  • Journal Title: BJPsych Open . Volume: 8(4) Issue: 4 Pages: 1-10
  • DOI: 10.1192/bjo.2022.50
  • Peer Reviewed / Open Access
• [Journal Article] Clinical moderators of response to nalmefene in a randomized-controlled trial for alcohol dependence: An exploratory analysis. (2022)
  • Author(s): Hashimoto N, Habu H, Takao S, Sakamoto S, Okahisa Y, Matsuo K, Takaki M, Kishi Y, Yamada N.
  • Journal Title: Drug Alcohol Depend. Volume: in press Pages: 109365-109365
  • DOI: 10.1016/j.drugalcdep.2022.109365
  • Peer Reviewed
• [Journal Article] Association between depression in chronic phase and future clinical outcome of patients with schizophrenia. (2022)
  • Author(s): Yamada Y, Yamauchi Y, Sakamoto S, Fujiwara M, Okahisa Y, Takao S, Takaki M, Yamada N.
  • Journal Title: Psychopharmacology (Berl) Volume: 239 Issue: 3 Pages: 965-975
  • DOI: 10.1007/s00213-022-06099-4
  • Peer Reviewed
• [Journal Article] A Decrease of Neutrophils After COVID-19 Vaccination in a Treatment-Resistant Patient With Schizophrenia Taking Clozapine. (2022)
  • Author(s): Takaki M, Yada Y, Sakamoto S, Fujiwara M, Okahisa Y, Yamada N.
  • Journal Title: J Clin Psychopharmacol. Volume: in press Issue: 3 Pages: 324-325
  • DOI: 10.1097/jcp.0000000000001527
  • Peer Reviewed
• [Journal Article] Mirtazapine Was Effective for a Patient With Benzodiazepine Dependence. (2022)
  • Author(s): Takaki M, Ishikawa R, Sakamoto S, Hashimoto N, Okahisa Y, Yamada N.
  • Journal Title: Clin Neuropharmacol. Volume: 45 Issue: 1 Pages: 11-12
  • DOI: 10.1097/wnf.0000000000000488
  • Peer Reviewed
• [Journal Article] Impairment of early neuronal maturation in anti-NMDA-receptor encephalitis. (2022)
  • Author(s): Okamoto S, Takaki M, Hinotsu K, Kawai H, Sakamoto S, Okahisa Y, Takao S, Tsutsui K, Kanbayashi T, Tanaka K, Yamada N.
  • Journal Title: Psychopharmacology (Berl) Volume: 239 Issue: 2 Pages: 525-531
  • DOI: 10.1007/s00213-021-06036-x
  • Peer Reviewed
• [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 Issue: 3 Pages: 227-237
  • DOI: 10.1111/acps.13264
  • Peer Reviewed / Open Access
• [Journal Article] Mechanisms Underlying the Comorbidity of Schizophrenia and Type 2 Diabetes Mellitus (2020)
  • Author(s): Mizuki Yutaka、Sakamoto Shinji、Okahisa Yuko、Yada Yuji、Hashimoto Nozomu、Takaki Manabu、Yamada Norihito
  • Journal Title: International Journal of Neuropsychopharmacology Volume: in press Issue: 5 Pages: 000-000
  • DOI: 10.1093/ijnp/pyaa097
  • NAID: 120007045004
  • 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 Issue: 1 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 Issue: 1 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 Hidekazu、Kushima Itaru、Mori Daisuke、Yoshimi Akira、Aleksic Branko、Nawa Yoshihiro、Toyama Miho、Furuta Sho、Yu Yanjie、Ishizuka Kanako、Kimura Hiroki、Arioka Yuko、Tsujimura Keita、Morikawa Mako、Okada Takashi、Inada Toshiya、Nakatochi Masahiro、Shinjo Keiko、Kondo Yutaka、Kaibuchi Kozo、Egawa Jun et al
  • Journal Title: Translational Psychiatry Volume: 10 Issue: 1 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) Issue: 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. (2019)
  • 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: Eur Neuropsychopharmacol. Volume: 29(9) Issue: 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: https://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 (2018)
  • 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: Schizophrenia Bulletin Volume: 印刷中 Issue: 4 Pages: 824-834
  • DOI: 10.1093/schbul/sby140
  • Peer Reviewed / Open Access
• [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: Translational Psychiatry Volume: 8 Issue: 1 Pages: 12-20
  • 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 Issue: 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) Issue: 5 Pages: 610-619
  • DOI: 10.1016/j.euroneuro.2018.03.004
  • Peer Reviewed / Open Access
• [Journal Article] A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder. (2017)
  • Author(s): Ikeda M, Shimasaki A, Takahashi A,et al.
  • Journal Title: Mol Psychiatry Volume: in press Issue: 3 Pages: 1-9
  • DOI: 10.1038/mp.2016.259
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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