Constructive understanding of stress-related psychiatric disorders by brain-gut-microbiota axis

• Project Area: Constructive understanding of multi-scale dynamism of neuropsychiatric disorders
• Project/Area Number: 21H00184
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Chiba University
• Principal Investigator: 橋本 謙二 千葉大学, 社会精神保健教育研究センター, 教授 (10189483)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2022: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: ストレス / レジリエンス / うつ病 / 腸内細菌 / 腸-脳相関 / 代謝物 / 脳ー腸相関 / 迷走神経 / 脳-腸相関

Outline of Research at the Start

可溶性エポキシド加水分解酵素（Ephx2）は、多価不飽和脂肪酸代謝に関わる酵素で、抗炎症作用を有するエポキシ脂肪酸を加水分解する酵素である。興味深い事に、Ephx2遺伝子欠損マウスは、社会的敗北ストレスを与えても、うつ様行動を示さないレジリエンスであった。またArid5a遺伝子欠損マウスは、社会的敗北ストレスを与えても、うつ様行動を示さないレジリエンスであった。本研究では、社会的敗北ストレスを施行してもうつ様行動を示さなかったEphx2遺伝子欠損マウスおよびArid5a遺伝子欠損マウスのレジリエンスの生物学的機序を脳-腸相関の視点から明らかにすることである。

Outline of Annual Research Achievements

ストレスは多くの精神疾患の発症に関係しているが、同じストレスを受けても個々の適応力の差で、精神疾患を発症する方と発症しない方が居る。実験動物においても、同じストレスを与えても、うつ様行動を示す動物とうつ様行動を示さない動物が存在する。今回、ラットに回避不能な電気ショックを足に与えて、うつ様行動を示すラットと示さないレジリエンスなラットに分けて、腸内細菌叢解析と血液中メタボローム解析を実施した。その結果、ストレス後の脆弱性とレジリエンスの違いに、腸内細菌叢や腸内細菌が生成する様々な代謝物が関係している可能性を見出した。
合成麻薬MDMAは、わが国をはじめとする多くの国において乱用が社会問題になっている違法薬物である。しかしながら、欧米では心理療法に加えてMDMAを投与することにより、重度のPTSD患者の症状を改善することが、第三相臨床治験で明らかになった。さらに、米国における疫学研究により、MDMA使用経験者は、その後、うつ病などの精神疾患を発症する割合が低くなることが報告された。今回、マウスを用いた試験で、MDMAを2週間投与したマウスは、その後、繰り返しのストレスを与えてもうつ様行動を示さず、レジリエンスであった。またMDMA投与によるレジリエンスに、腸内細菌叢が関与している可能性を報告した。
このように、ストレス後の精神疾患発症の違いには、腸内細菌叢を介する腸-脳相関が関与している可能性があることを見出した。

Research Progress Status

令和4年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和4年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] 鄭州大学/四川大学/同済医学院(中国)
• [Int'l Joint Research] University of California at Davis(米国)
• [Journal Article] Key role of the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve in demyelination of the cuprizone-treated mouse brain (2023)
  • Author(s): Wang X, Eguchi A, Yang Y, Chang L, Wan X, Shan J, Qu Y, Ma L, Mori C, Yang J, Hashimoto K
  • Journal Title: Neurobiol Dis Volume: 176 Pages: 105951-105951
  • DOI: 10.1016/j.nbd.2022.105951
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Repeated use of 3,4-methylenedioxymethamphetamine is associated with the resilience in mice after chronic social defeat stress: A role of gut-microbiota-brain axis (2023)
  • Author(s): Qu Y, Eguchi A, Wan X, Ma L, Chang L, Shan J, Yang Y, Mori C, Hashimoto K
  • Journal Title: Psychiatry Res Volume: 320 Pages: 115020-115020
  • DOI: 10.1016/j.psychres.2022.115020
  • Peer Reviewed / Open Access
• [Journal Article] Arketamine for cognitive impairment in psychiatric disorders (2023)
  • Author(s): Hashimoto K
  • Journal Title: Eur Arch Psychiatry Clin Neurosci Volume: in press Issue: 7 Pages: 1513-1525
  • DOI: 10.1007/s00406-023-01570-5
  • Peer Reviewed / Open Access
• [Journal Article] Beneficial effects of arketamine on the reduced bone mineral density in susceptible mice after chronic social defeat stress: Role of the gut-microbiota-bone-brain axis (2023)
  • Author(s): Wan X, Eguchi A, Chang L, Mori C, Hashimoto K
  • Journal Title: Neuropharmacology Volume: 228 Pages: 109466-109466
  • DOI: 10.1016/j.neuropharm.2023.109466
  • Peer Reviewed
• [Journal Article] Abnormal compositions of gut microbiota and metabolites are associated with susceptibility versus resilience in rats to inescapable electric stress (2023)
  • Author(s): Wang X, Eguchi A, Fujita Y, Wan X, Chang L, Yang Y, Shan J, Qu Y, Ma L, Shirayama Y, Mori C, Yang J, Hashimoto K
  • Journal Title: J Affect Disord Volume: 331 Pages: 369-379
  • DOI: 10.1016/j.jad.2023.03.073
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Gut-microbiota-brain axis by bile acids in depression (2022)
  • Author(s): Hashimoto K
  • Journal Title: Psychiatry Clin Neurosci. Volume: 76(7) Issue: 7 Pages: 281-281
  • DOI: 10.1111/pcn.13370
  • Peer Reviewed
• [Journal Article] Gut-microbiota-brain axis in the vulnerability to psychosis in adulthood after repeated cannabis exposure during adolescence (2022)
  • Author(s): Wan X, Eguchi A, Qu Y, Yang Y, Chang L, Shan J, Mori C, Hashimoto K
  • Journal Title: Eur Arch Psychiatry Clin Neurosci Volume: 272(7) Issue: 7 Pages: 1297-1309
  • DOI: 10.1007/s00406-022-01437-1
  • Peer Reviewed
• [Journal Article] Fecal microbiota transplantation from patients with rheumatoid arthritis causes depression-like behaviors in mice through abnormal T cells activation (2022)
  • Author(s): Pu Y, Zhang Q, Tang Z, Lu C, Wu L, Zhong Y, Chen Y, Hashimoto K, Luo Y, Liu Y
  • Journal Title: Transl Psychiatry Volume: 12(1) Issue: 1 Pages: 223-223
  • DOI: 10.1038/s41398-022-01993-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 10.1016/j.neubiorev.2022.104762 (2022)
  • Author(s): Wang X, Yang J, Hashimoto K
  • Journal Title: Neurosci Biobehav Rev Volume: 139 Pages: 104762-104762
  • DOI: 10.1016/j.neubiorev.2022.104762
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long-lasting beneficial effects of maternal intake of sulforaphane glucosinolate on gut microbiota in adult offspring (2022)
  • Author(s): Wei Y, Chang L, Liu G, Wang X, Yang Y, Hashimoto K
  • Journal Title: J Nutr Biochem Volume: 109 Pages: 109098-109098
  • DOI: 10.1016/j.jnutbio.2022.109098
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The gut-liver axis in sepsis: interaction mechanisms and therapeutic potential (2022)
  • Author(s): Zhang X, Liu H, Hashimoto K, Yuan S, Zhang J
  • Journal Title: Crit Care Volume: 26(1) Issue: 1 Pages: 23-23
  • DOI: 10.1186/s13054-022-04090-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Depression-like behaviors in mouse model of Sjogren's syndrome: A role of gut-microbiota-brain axis (2022)
  • Author(s): Pu Y, He Y, Zhao X, Zhang Q, Wen J, Hashimoto K, Liu Y
  • Journal Title: Pharmacol Biochem Behav Volume: 219 Pages: 173448-173448
  • DOI: 10.1016/j.pbb.2022.173448
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effects of spleen nerve denervation on depression-like phenotype, systemic inflammation, and abnormal composition of gut microbiota in mice after administration of lipopolysaccharide: A role of brain-spleen axis (2022)
  • Author(s): Ma L, Zhang J, Fujita Y, Shinno-Hashimoto H, Shan J, Wan X, Qu Y, Chang L, Wang X, Hashimoto K
  • Journal Title: J Affect Disord Volume: 317 Pages: 156-165
  • DOI: 10.1016/j.jad.2022.08.087
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A role of gut-microbiota-brain axis via subdiaphragmatic vagus nerve in depression-like phenotypes in Chrna7 knock-out mice (2022)
  • Author(s): Yang Y, Eguchi A, Wan X, Chang L, Wang X, Qu Y, Mori C, Hashimoto K
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry Volume: 120 Pages: 110652-110652
  • DOI: 10.1016/j.pnpbp.2022.110652
  • Peer Reviewed
• [Journal Article] Impact of broad-spectrum antibiotics on the gut-microbiota-spleen-brain axis (2022)
  • Author(s): Wan X, Eguchi A, Sakamoto A, Fujita Y, Yang Y, Qu Y, Hatano M, Mori C, Hashimoto K
  • Journal Title: Brain Behav Immun Health Volume: 27 Pages: 100573-100573
  • DOI: 10.1016/j.bbih.2022.100573
  • Peer Reviewed / Open Access
• [Journal Article] (R)-ketamine ameliorates demyelination and facilitates remyelination in cuprizone-treated mice: A role of gut-microbiota-brain axis (2022)
  • Author(s): Wang X, Chang L, Wan X, Tan Y, Qu Y, Shan J, Yang Y, Ma L, Hashimoto K.
  • Journal Title: Neurobiol Dis Volume: 165 Pages: 105635-105635
  • DOI: 10.1016/j.nbd.2022.105635
  • Peer Reviewed / Open Access
• [Journal Article] Brain-gut-microbiota axis in depression: A historical overview and future directions (2022)
  • Author(s): Chang L, Wei Y, Hashimoto K.
  • Journal Title: Brain Res Bull Volume: 182 Pages: 44-56
  • DOI: 10.1016/j.brainresbull.2022.02.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Brain-spleen axis in health and diseases: A review and future perspective (2022)
  • Author(s): Wei Y, Wang T, Liao L, Fan X, Chang L, Hashimoto K.
  • Journal Title: Brain Res Bull Volume: 182 Pages: 130-140
  • DOI: 10.1016/j.brainresbull.2022.02.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ingestion of Faecalibaculum rodentium causes depression-like phenotypes in resilient Ephx2 knock-out mice: A role of brain-gut-microbiota axis via the subdiaphragmatic vagus nerve (2021)
  • Author(s): Wang S, Ishima T, Qu Y, Shan J, Chang L, Wei Y, Zhang J, Pu Y, Fujita Y, Tan Y, Wang X, Ma L, Wan X, Hammock BD, Hashimoto K
  • Journal Title: J Affect Disord Volume: 292 Pages: 565-573
  • DOI: 10.1016/j.jad.2021.06.006
  • Peer Reviewed / Int'l Joint Research