消化管粘膜免疫が左右するバクテリアル・トランスロケーションと全身感染

• Project/Area Number: 19K08961
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54030:Infectious disease medicine-related
• Research Institution: International University of Health and Welfare
• Principal Investigator: 松本 哲哉 国際医療福祉大学, 医学部, 主任教授 (10256688)
• Project Period (FY): 2019-04-01 – 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 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: プロバイオティクス / バクテリアル・トランスロケーション / 免疫活性 / 薬剤耐性 / 耐性菌 / 選択的増殖 / 消化管粘膜免疫 / 全身感染

Outline of Research at the Start

本研究は、消化管からのバクテリアル・トランスロケーションの過程でどのようにプロバイオティクスが消化管粘膜免疫に作用し、さらに全身感染に発展させる要因について検討することを目的としている。近年、癌化学療法の進歩や臓器移植の増加に伴い、免疫不全患者における感染症の制御は重要な課題となっている。私達のこれまでの研究では、一部のプロバイオティクス株はむしろ全身感染を増悪させ、その病態に粘膜免疫が関与していることが示唆された。そのため、消化管粘膜免疫の活性化が負の方向に感染を導く可能性を含めて、その機序を解明することを目的としている。

Outline of Annual Research Achievements

本研究はプロバイオティクス等による消化管粘膜免疫を活性化や腸管内常在菌としての感染防御効果が必ずしも生体に有利な作用をもたらさず、時には致死率の上昇などを起こし得ることを確認することが目的となっている。プロバイオティクスはすでに腸管からのバクテリアル・トランスロケーションの抑制効果をもたらすことがこれまでの研究で示されているが、その機序としては消化管免疫の活性化や消化管上皮の障害の回避があげられる。私達は免疫誘導活性の強い乳酸菌株を菌株バンクであるJCM（Japan Collection of Microorganisms）より入手し、マウスの腸管由来敗血症モデルを用いた検討を行い、活性化の程度が高まると、逆に腸管の炎症が強まり、生体に不利に働くことを示した。さらに薬剤耐性を示す菌株が腸管内に常在した際に、抗菌薬投与後にどのような影響をもたらすかについて確認したところ、経口的に投与された耐性菌の菌株は経時的に減少したものの、その後、抗菌薬が投与された後で、菌量の増加をもたらし、バクテリアル・トランスロケーションのリスクが高まることが明らかとなった。これらの結果から、通常の臨床の現場において使用される一般的なプロバイオティクスの薬剤については明らかな懸念点はないと考えられるが、その一方で、過剰な免疫誘導活性や薬剤耐性はバクテリアル・トランスロケーションおよびその後の感染の重症化につながる可能性が示唆された。

Research Products

• [Journal Article] Burden of Antimicrobial Resistance in Japan: A Systematic Literature Review and Meta-Analysis (2024)
  • Author(s): Matsumoto Tetsuya、Yuasa Akira、Matsuda Hiroyuki、Ainiwaer Dilinuer、Yonemoto Naohiro
  • Journal Title: Infectious Diseases and Therapy Volume: 25 Issue: 5 Pages: 49-56
  • DOI: 10.1007/s40121-024-00960-z
  • Peer Reviewed
• [Journal Article] Fourth national Japanese antimicrobial susceptibility pattern surveillance program: Bacterial isolates from patients with complicated urinary tract infections (2024)
  • Author(s): Kobayashi K, Takahashi S, Yasuda M, Miyazaki J, Wada K, Matsumoto M, Hayami H, Yamamoto S, Kiyota H, Sato J, Matsumoto T, et al.
  • Journal Title: Journal of Infection and Chemotherapy Volume: 24 Issue: 7 Pages: 1341-1349
  • DOI: 10.1016/j.jiac.2024.03.024
  • Peer Reviewed / Open Access
• [Journal Article] Third nationwide surveillance of bacterial pathogens in patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2020 and 2021: Antimicrobial susceptibility of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus saprophyticus (2024)
  • Author(s): Wada K, Tsuboi I, Takahashi S, Yasuda M, Miyazaki J, Kobayashi K, Matsumoto M, Hayami H, Yamamoto S, Kiyota H, Sato J, Matsumoto T, et al.
  • Journal Title: Journal of Infection and Chemotherapy Volume: 30 Issue: 4 Pages: 277-285
  • DOI: 10.1016/j.jiac.2024.01.011
  • Peer Reviewed / Open Access
• [Journal Article] A Multicenter Randomized Controlled Trial To Evaluate the Efficacy and Safety of Nelfinavir in Patients with Mild COVID-19 (2023)
  • Author(s): Miyazaki T, Hosogaya N, Fukushige Y, Takemori S, Morimoto S, Yamamoto H, Hori M, Ozawa Y, Shiko Y, Inaba Y, Kurokawa T, Matsumoto T, Saito M, Yotsuyanagi H, Kohno S. et al.
  • Journal Title: Microbiology Spectrum Volume: 11 Issue: 3 Pages: 4311-4322
  • DOI: 10.1128/spectrum.04311-22
  • Peer Reviewed / Open Access
• [Journal Article] The third nationwide surveillance of antimicrobial susceptibility against Neisseria gonorrhoeae from male urethritis in Japan, 2016?2017 (2023)
  • Author(s): Yasuda M、Takahashi S、Miyazaki J、Wada K、Kobayashi K、Matsumoto M、Hayami H、Yamamoto S、Kiyota H、Sato J、Matsumto T、et al.
  • Journal Title: Journal of Infection and Chemotherapy Volume: 29 Issue: 11 Pages: 1011-1016
  • DOI: 10.1016/j.jiac.2023.08.003
  • Peer Reviewed / Open Access
• [Journal Article] Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2019?2020: General view of the pathogens' antibacterial susceptibility (2023)
  • Author(s): Tokimatsu I, Matsumoto T, Tsukada H, et al.
  • Journal Title: Journal of Infection and Chemotherapy Volume: 29 Issue: 8 Pages: 731-743
  • DOI: 10.1016/j.jiac.2023.04.008
  • Peer Reviewed / Open Access
• [Journal Article] Urban Microbiomes in Narita, Chiba, Japan: Shotgun Metagenome Sequences of a Train Station (2023)
  • Author(s): Rasmika Dewi Dewa A. P.、Shiwa Yuh、Ryon Krista、Mason Christopher E.、Matsumoto Tetsuya、Suzuki Haruo
  • Journal Title: Microbiology Resource Announcements Volume: 12 Issue: 1 Pages: 22-30
  • DOI: 10.1128/mra.01092-22
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Long Term Follow-Up Study of a Randomized, Open-Label, Uncontrolled, Phase I/II Study to Assess the Safety and Immunogenicity of Intramuscular and Intradermal Doses of COVID-19 DNA Vaccine (AG0302-COVID19) (2023)
  • Author(s): Nakagami Hironori、Matsumoto Tetsuya、Takazawa Kenji、Sekino Hisakuni、Matsuoka Osamu、Inoue Satoshi、Furuie Hidetoshi、Morishita Ryuichi
  • Journal Title: Vaccines Volume: 11 Issue: 10 Pages: 1535-1535
  • DOI: 10.3390/vaccines11101535
  • Peer Reviewed / Open Access
• [Journal Article] An Economic Evaluation Estimating the Clinical and Economic Burden of Increased Vancomycin-Resistant Enterococcus faecium Infection Incidence in Japan (2023)
  • Author(s): Sugai Motoyuki、Yuasa Akira、Miller Ryan L.、Vasilopoulos Vasileios、Kurosu Hitomi、Taie Amer、Gordon Jason P.、Matsumoto Tetsuya
  • Journal Title: Infectious Diseases and Therapy Volume: 12 Issue: 6 Pages: 1695-1713
  • DOI: 10.1007/s40121-023-00826-w
  • Peer Reviewed
• [Journal Article] Estimating the Economic and Clinical Value of Introducing Ceftazidime/Avibactam into Antimicrobial Practice in Japan: A Dynamic Modelling Study (2023)
  • Author(s): Matsumoto Tetsuya、Yuasa Akira、Miller Ryan、Pritchard Clive、Ohashi Takahisa、Taie Amer、Gordon Jason
  • Journal Title: PharmacoEconomics - Open Volume: 7 Issue: 1 Pages: 65-76
  • DOI: 10.1007/s41669-022-00368-w
  • Peer Reviewed
• [Journal Article] Correction to: An Economic Evaluation Estimating the Clinical and Economic Burden of Increased Vancomycin-Resistant Enterococcus faecium Infection Incidence in Japan (2023)
  • Author(s): Sugai Motoyuki、Yuasa Akira、Miller Ryan L.、Vasilopoulos Vasileios、Kurosu Hitomi、Taie Amer、Gordon Jason P.、Matsumoto Tetsuya
  • Journal Title: Infectious Diseases and Therapy Volume: 12 Issue: 8 Pages: 2191-2192
  • DOI: 10.1007/s40121-023-00853-7
  • Peer Reviewed
• [Journal Article] Corrigendum to “The second nationwide surveillance of antibacterial susceptibility patterns of pathogens isolated from skin and soft-tissue infections in dermatology departments in Japan” [J. Infect. Chemother. 29 (2023) 143?149] (2023)
  • Author(s): Ohnishi T, Watanabe S, Matsumoto T, et al.
  • Journal Title: Journal of Infection and Chemotherapy Volume: 29 Issue: 6 Pages: 634-635
  • DOI: 10.1016/j.jiac.2023.03.014
  • Peer Reviewed
• [Journal Article] The second nationwide surveillance of antibacterial susceptibility patterns of pathogens isolated from skin and soft-tissue infections in dermatology departments in Japan (2023)
  • Author(s): Ohnishi Takamitsu、Okuyama Ryuhei、Ikeda Masami
  • Journal Title: Journal of Infection and Chemotherapy Volume: 29 Issue: 2 Pages: 143-149
  • DOI: 10.1016/j.jiac.2022.10.005
  • Peer Reviewed
• [Journal Article] Emergency Vaccination as a Control Strategy against Sheeppox Outbreak in a Highly Susceptible Population (2022)
  • Author(s): Oreiby A, Seada AS, Abou Elazab MF, Abdo W, Kassab M, Hegazy Y, Khalifa HO, Matsumoto T.
  • Journal Title: Animals Volume: 12 Issue: 16 Pages: 2084-2084
  • DOI: 10.3390/ani12162084
  • Peer Reviewed / Open Access
• [Journal Article] Review on Bovine Tuberculosis: An Emerging Disease Associated with Multidrug-Resistant Mycobacterium Species. (2022)
  • Author(s): Borham M, Oreiby A, El-Gedawy A, Hegazy Y, Khalifa HO, Al-Gaabary M, Matsumoto T.
  • Journal Title: Pathogens Volume: 11 Issue: 7 Pages: 715-715
  • DOI: 10.3390/pathogens11070715
  • Peer Reviewed / Open Access
• [Journal Article] Distribution of extraintestinal pathogenic Escherichia coli O-serotypes and antibiotic resistance in blood isolates collected from patients in a surveillance study in Japan (2022)
  • Author(s): Matsumoto T, Mikamo H, Ohge H, Yanagihara K, Weerdenburg E, Go O, Spiessens B, van Geet G, van den Hoven T, Momose A, Hagiwara Y, Nakayama Y, Poolman J, Geurtsen J, Kaku M.
  • Journal Title: J Infect Chemother Volume: 28 Issue: 11 Pages: 1445-1451
  • DOI: 10.1016/j.jiac.2022.07.001
  • Peer Reviewed
• [Journal Article] Immunological responses following the third dose of the BNT162b2 SARS-CoV-2 vaccine among Japanese healthcare workers (2022)
  • Author(s): Tamura M, Fujita R, Sato T, Sato R, Kato Y, Nagasawa M, Matsumoto T.
  • Journal Title: J Infect Chemother Volume: 28 Issue: 11 Pages: 1478-1482
  • DOI: 10.1016/j.jiac.2022.07.006
  • Peer Reviewed
• [Journal Article] Comparative characteristics of the background and blood test findings in adults with pneumococcal pneumonia and invasive pneumococcal disease: A retrospective study (2021)
  • Author(s): Tsuchiya M, Miyazaki H, Takata M, Shibuya R, Chang B, Ubukata K, Matsumoto T, Nakamura S.
  • Journal Title: J Infect Chemother. Volume: 28 Issue: 3 Pages: 420-425
  • DOI: 10.1016/j.jiac.2021.12.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Estimating the Economic and Clinical Value of Reducing Antimicrobial Resistance to Three Gram-negative Pathogens in Japan (2021)
  • Author(s): Matsumoto T, Darlington O, Miller R, Gordon J, McEwan P, Ohashi T, Taie A, Yuasa A.
  • Journal Title: J Health Econ Outcomes Res Volume: 8 Issue: 2 Pages: 64-75
  • DOI: 10.36469/001c.28327
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nationwide surveillance of the antimicrobial susceptibility of Chlamydia trachomatis from male urethritis in Japan: Comparison with the first surveillance report (2021)
  • Author(s): Takahashi S, Yasuda M, Wada K, Matsumoto M, Hayami H, Kobayashi K, Miyazaki J, Kiyota H, Matsumoto T
  • Journal Title: J Infect Chemother Volume: 28 Issue: 1 Pages: 1-5
  • DOI: 10.1016/j.jiac.2021.09.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High β-Lactam and Quinolone Resistance of Enterobacteriaceae from the Respiratory Tract of Sheep and Goat with Respiratory Disease (2021)
  • Author(s): Khalifa HO, Oreiby A, Abd El-Hafeez AA, Abd El Latif A, Okanda T, Kato Y, Matsumoto T.
  • Journal Title: Animals Volume: 11 Issue: 8 Pages: 2258-2258
  • DOI: 10.3390/ani11082258
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The background occurrence of selected clinical conditions prior to the start of an extensive national vaccination program in Japan (2021)
  • Author(s): Sobue T, Fukuda H, Matsumoto T, Lee B, Ito S, Iwata S.
  • Journal Title: PLoS One Volume: 16 Issue: 8 Pages: e0256379-e0256379
  • DOI: 10.1371/journal.pone.0256379
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Efficacy of Phage Therapy in a Murine Model of Pseudomonas aeruginosa Pneumonia and Sepsis (2021)
  • Author(s): Yang X, Haque A, Matsuzaki S, Matsumoto T, Nakamura S.
  • Journal Title: Front Microbiol Volume: 12 Pages: 682255-682255
  • DOI: 10.3389/fmicb.2021.682255
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Change in antimicrobial susceptibility of pathogens isolated from surgical site infections over the past decade in Japanese nation-wide surveillance study (2021)
  • Author(s): Ueda T、Takesue Y、Matsumoto T、Tateda K、Kusachi S、Mikamo H、Sato J、Hanaki H、Mizuguchi T、Morikane K、Kobayashi M、Harihara Y、Seki S、Ishida Y、Fukushima R、Hada M、Matsuo Y、Kubo S、Kimura Y、Hata H、Nakajima K、Ohge H、Akagi S、Takeda S、Fukui Y、Suzuki K、Okamoto K、Yanagihara K、Kawamura H
  • Journal Title: Journal of Infection and Chemotherapy Volume: 27 Issue: 7 Pages: 931-939
  • DOI: 10.1016/j.jiac.2021.03.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High β-lactam resistance in Gram-negative bacteria associated with kennel cough and cat flu in Egypt (2021)
  • Author(s): Khalifa HO, Oreiby AF, Okanda T, Kato Y, Matsumoto T.
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 3347-3347
  • DOI: 10.1038/s41598-021-82061-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characteristics of Carbapenemase-Producing Klebsiella pneumoniae Isolated in the Intensive Care Unit of the Largest Tertiary Hospital in Bangladesh (2021)
  • Author(s): Takashi Okanda, Anwarul Haque, Hiromu Takemura, Tetsuya Matsumoto
  • Journal Title: Front Microbiol. Volume: 11 Pages: 61-70
  • DOI: 10.3389/fmicb.2020.612020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] First Report of Foodborne Klebsiella pneumoniae Coharboring blaVIM-1, blaNDM-1, and mcr-9 (2020)
  • Author(s): Khalifa Hazim O.、Soliman Ahmed M.、Saito Takashi、Kayama Shizuo、Yu Liansheng、Hisatsune Junzo、Sugai Motoyuki、Nariya Hirofumi、Ahmed Ashraf M.、Shimamoto Toshi、Matsumoto Tetsuya、Shimamoto Tadashi
  • Journal Title: Antimicrobial Agents and Chemotherapy Volume: 64 Issue: 9 Pages: 882-890
  • DOI: 10.1128/aac.00882-20
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prevalence and antimicrobial resistance of Shiga toxin-producing Escherichia coli in milk and dairy products in Egypt. (2020)
  • Author(s): lafify M, Khalifa HO, Al-Ashmawy M, Elsherbini M, El Latif AA, Okanda T, Matsumoto T, Koseki S, Abdelkhalek A.
  • Journal Title: J Environ Sci Health B. Volume: 3 Issue: 3 Pages: 265-272
  • DOI: 10.1080/03601234.2019.1686312
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] High Prevalence of Antimicrobial Resistance in Gram-Negative Bacteria Isolated from Clinical Settings in Egypt: Recalling for Judicious Use of Conventional Antimicrobials in Developing Nations (2019)
  • Author(s): Khalifa Hazim O.、Soliman Ahmed M.、Ahmed Ashraf M.、Shimamoto Toshi、Nariya Hirofumi、Matsumoto Tetsuya、Shimamoto Tadashi
  • Journal Title: Microbial Drug Resistance Volume: 25 Issue: 3 Pages: 371-385
  • DOI: 10.1089/mdr.2018.0380
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Slightly acidic electrolyzed water disrupts biofilms and effectively disinfects Pseudomonas aeruginosa. (2019)
  • Author(s): Okanda T, Takahashi R, Ehara T, Ohkusu K, Furuya N, Matsumoto T.
  • Journal Title: J Infect Chemother. Volume: 6 Issue: 6 Pages: 452-457
  • DOI: 10.1016/j.jiac.2019.01.014
  • Peer Reviewed
• [Presentation] 近年に上市された抗微生物薬について (2023)
  • Author(s): 松本 哲哉
  • Organizer: 第97回日本感染症学会総会・学術講演会. 第71回日本化学療法学会学術集会 合同学会
  • Invited
• [Presentation] 日本化学療法学会,および日本臨床微生物学会の対応 (2023)
  • Author(s): 松本 哲哉
  • Organizer: 第97回日本感染症学会総会・学術講演会. 第71回日本化学療法学会学術集会 合同学会
  • Invited
• [Presentation] 一般診療に与える感染症の影響 新型コロナウイルス感染症を振り返って (2023)
  • Author(s): 松本 哲哉
  • Organizer: 第25回日本褥瘡学会学術集会
  • Invited
• [Presentation] 新型コロナウイルス感染症の振り返りとこれからの対応 (2023)
  • Author(s): 松本 哲哉
  • Organizer: 第120回 日本保険医学会定時総会
  • Invited
• [Presentation] 腸内細菌の新たな知見と臨床での活用法 (2023)
  • Author(s): 松本 哲哉
  • Organizer: 第3回日本耳鼻咽喉科免疫アレルギー感染症学会総会・学術講演会
  • Invited
• [Presentation] AMR対策に貢献できる 肺炎予防 (2019)
  • Author(s): 松本哲哉
  • Organizer: 第93回日本感染症学会総会・学術講演会 教育講演
  • Invited
• [Presentation] 感染症遺伝子検査のこれから (2019)
  • Author(s): 松本哲哉
  • Organizer: 第93回日本感染症学会総会・学術講演会 教育講演
  • Invited
• [Presentation] 高齢者肺炎とインフルエンザ予防の重要性 (2019)
  • Author(s): 松本哲哉
  • Organizer: 第６８回日本感染症学会東日地方会・第６６回日本化学療法学会東日本支部
  • Invited
• [Book] Up-to-date子どもの感染症 (2023)
  • Author(s): 松本 哲哉
  • Total Pages: 48
  • Publisher: メディカルレビュー社
• [Book] 呼吸器ジャーナル (2023)
  • Author(s): 松本 哲哉
  • Total Pages: 138
  • Publisher: 医学書院
• [Book] 病体生理 (2023)
  • Author(s): 松本 哲哉
  • Total Pages: 38
  • Publisher: 病体生理研究所
• [Book] 肝胆膵 (2023)
  • Author(s): 松本 哲哉
  • Total Pages: 82
  • Publisher: アークメディア