Study of stress-related psychiatric disorders based on brain-gut axis via vagus nerve

• Project Area: Glia decoding: deciphering information critical for brain-body interactions
• Project/Area Number: 21H05612
• Research Category: Grant-in-Aid for Transformative Research Areas (A)
• Allocation Type: Single-year Grants
• Review Section: Transformative Research Areas, Section (III)
• 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): 2021-09-10 – 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: 炎症 / ストレス / うつ病 / 腸内細菌 / 腸-脳相関 / 迷走神経 / 代謝物 / 脳ー腸相関 / レジリエンス / うつ症状 / ストレス性精神障害

Outline of Research at the Start

ストレスは多くの精神疾患の発症に関係している。また同じストレスを受けても、個々の適応力の差で、脆弱性とレジリエンスに分かれるが、これらの二つの違いを説明できる生物学的機序は明らかでない。応募者らは、これまでストレス後の脆弱性とレジリエンスに、迷走神経を介する脳-腸相関が重要な役割を果たしている事を報告した。本研究において、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遺伝子欠損マウスを用いて、脆弱性・レジリエンスの生物学的機序を迷走神経を介する脳-腸相関と脳グリア細胞の視点から明らかにする。

Outline of Annual Research Achievements

炎症はうつ病などの精神疾患の発症に深く関わっている。一方、近年話題になっている腸-脳相関は、腸内細菌が生成する様々な代謝物を介して、身体の恒常性維持や様々な疾患の発症に関与している。またストレス等による腸内細菌叢および代謝物の異常が炎症を引き起こし、うつ病などの精神疾患の発症に繋がると推測されている。
ニコチン受容体のサブタイプの一つであるα7ニコチン受容体は、脳だけでなく、末梢の炎症に重要な役割を担っている。以前我々は、α7ニコチン受容体遺伝子欠損マウスが炎症を示し、うつ様行動を示すことを報告した。今回、うつ様行動を示すα7ニコチン受容体遺伝子欠損マウスの腸内細菌（糞）を野生型マウス（抗生剤処置）に経口投与するとうつ様行動を示す事、また横隔膜下の迷走神経を切断すると腸内細菌（糞）を投与してもうつ様行動を示さないことを報告した。さらに、うつ様行動を示すα7ニコチン受容体遺伝子欠損マウスの横隔膜下の迷走神経を切断するとうつ様行動を示さないこと、また腸内細菌や細菌が生成する代謝物の関与が示唆された。今回の研究成果は、迷走神経を介する腸-脳相関がα7ニコチン受容体遺伝子欠損マウスのうつ様行動に関係していることを見出した。
クプリゾンを含む餌をマウスに与えると、脳において脱髄が生じ、多発性硬化症のモデル動物として使用される。今回、横隔膜下の迷走神経を切断すると、クプリゾンを含む餌を与えても、脳における脱髄が生じないことを見出し、この作用に腸内細菌が生成する代謝物を含む腸-脳相関が寄与している可能性を報告した。
本研究結果から、様々な中枢神経系の疾患の発症には、迷走神経を介する腸-脳相関が重要な役割を果たしている可能性を見出した。

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] Southwest University(中国)
• [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] Effects of (R)-ketamine on reduced bone mineral density in ovariectomized mice: A role of gut microbiota (2022)
  • Author(s): Wan X, Eguchi A, Fujita Y, Ma L, Wang X, Yang Y, Qu Y, Chang L, Zhang J, Mori C, Hashimoto K
  • Journal Title: Neuropharmacology Volume: 213 Pages: 109139-109139
  • DOI: 10.1016/j.neuropharm.2022.109139
  • Peer Reviewed / Int'l Joint Research
• [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] 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] 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] 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] Microglial depletion and abnormalities in gut microbiota composition and short-chain fatty acids in mice after repeated administration of colony stimulating factor 1 receptor inhibitor PLX5622 (2022)
  • Author(s): Yang Y, Ishima T, Wan X, Wei Y, Chang L, Zhang J, Qu Y, Hashimoto K.
  • Journal Title: Eur Arch psychiatry Clin Neurosci Volume: 272(3) Issue: 3 Pages: 483-495
  • DOI: 10.1007/s00406-021-01325-0
  • Peer Reviewed
• [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