Analysis of the mechanism of colonization resistance against pathogenic fungi mediated by commensal bacteria and group3 innate lymphoid cells

• Project/Area Number: 19H03465
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49050:Bacteriology-related
• Research Institution: Chiba University
• Principal Investigator: Goto Yoshiyuki 千葉大学, 真菌医学研究センター, 准教授 (10755523)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2021: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2020: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2019: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 腸内細菌 / Candida albicans / 腸管免疫 / 真菌

Outline of Research at the Start

Candida albicansは腸管内で常在する真菌であるが、腸内細菌叢の攪乱や宿主の免疫力が低下した状況では腸管内で異常に増殖し、危険な感染症の一つである侵襲性カンジダ感染症の要因となる。本研究では、腸内細菌と自然免疫細胞の一つである3型自然リンパ球に着目し、腸管におけるC. albicansの定着・増殖抑制機構の解明を試みる。特に嫌気培養装置を用いて腸内細菌を分離し、C. albicansの増殖を抑制する腸内細菌および腸内細菌由来因子を同定する。本研究は微生物の腸内定着機構という生物学的に重要な意義を有するのみならず、腸内細菌を応用した予防・診断・治療法の開発に繋がることも期待される。

Outline of Final Research Achievements

In this study, we tried to identify the roles of intestinal commensal bacteria and host immune cells that inhibit intestinal colonization of pathogenic fungi. As a result, we found that specific intestinal bacteria inhibit the intestinal colonization of Candida albicans in vivo. The specific commensal bacteria produced a water-soluble facors that inhibits the growth of other several Candida species. Furthermore, it was identified that group 3 innate lymphoid cells inhibit the intestinal colonization of C. albicans by promoting the formation of secondary lymphoid organs through LTa and inducing the differentiation and proliferation of CD4 positive T cells. From these results, it is identified that intestinal bacteria and host immune cells play a protective barrier system that inhibits intestinal colonization of pathogenic fungi.

Academic Significance and Societal Importance of the Research Achievements

腸内細菌は種々の病原性微生物の腸管定着を阻害する効果、”colonization resistance”効果を有することは以前より知られていたものの、そのメカニズムの多くは不明であった。本研究により、腸内細菌よる病原性真菌の定着阻害機構の一端が明らかとなった。さらに、宿主免疫細胞も病原性真菌の定着を阻害していることを明らかになった。病原性真菌は、HIV感染、臓器移植、抗ガン剤投与患者、高齢者など免疫力が低下したヒトにおいて、難治性感染症である侵襲性真菌症を誘導する微生物であり、本研究において見出した知見が新規抗真菌治療方法の確立に繋がることが期待される。

Research Products

• [Int'l Joint Research] ミシガン大学/イリノイ大学(米国)
• [Int'l Joint Research] コロンビア大学/ミシガン大学/イリノイ大学(米国)
• [Journal Article] Unique symbiont-derived sphingolipids: Dietary amino acids source branch formation. (2022)
  • Author(s): Goto Y.
  • Journal Title: Cell Host Microbe Volume: 30 Issue: 1 Pages: 3-5
  • DOI: 10.1016/j.chom.2021.12.015
• [Journal Article] 腸管上皮細胞が発現する糖鎖を介した腸管恒常性制御機構 (2022)
  • Author(s): 後藤 義幸
  • Journal Title: 基礎老化研究誌 Volume: 46 Pages: 11-15
  • Peer Reviewed
• [Journal Article] Editorial: Regulation of Immunity by Non-Immune Cells. (2021)
  • Author(s): Dainichi T, Kabashima K, Ivanov II, Goto Y.
  • Journal Title: Front Immunol Volume: 12 Pages: 770847-770847
  • DOI: 10.3389/fimmu.2021.770847
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 腸内細菌とTh17細胞 (2021)
  • Author(s): 後藤 義幸
  • Journal Title: 腸内細菌学雑誌 Volume: 35 Pages: 215-222
  • NAID: 130008112166
  • Peer Reviewed
• [Journal Article] Measurement of the Intestinal pH in Mice under Various Conditions Reveals Alkalization Induced by Antibiotics (2021)
  • Author(s): Shimizu Kouki、Seiki Issei、Goto Yoshiyuki、Murata Takeshi
  • Journal Title: Antibiotics Volume: 10 Issue: 2 Pages: 180-180
  • DOI: 10.3390/antibiotics10020180
  • Peer Reviewed / Open Access
• [Journal Article] Subtilase cytotoxin induces a novel form of Lipocalin 2, which promotes Shiga-toxigenic Escherichia coli survival. (2020)
  • Author(s): Yahiro, K., Ogura, K., Goto, Y., Iyoda, S., Kobayashi, T., Takeuchi, H., Ohnishi, M., Moss, J.
  • Journal Title: Scientific Reports. Volume: 10 Issue: 1 Pages: 18943-18943
  • DOI: 10.1038/s41598-020-76027-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Interleukin-22-mediated host glycosylation prevents Clostridioides difficile infection by modulating the metabolic activity of the gut microbiota (2020)
  • Author(s): Nagao-Kitamoto Hiroko, Fukuda Shinji, Higgins Peter D. R., Karlsson Niclas G., Young Vincent B., Kamada Nobuhiko, et al
  • Journal Title: Nature Medicine Volume: 26 Issue: 4 Pages: 608-617
  • DOI: 10.1038/s41591-020-0764-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 重症病態における腸内細菌叢と免疫系のかかわり (2020)
  • Author(s): 後藤 義幸
  • Journal Title: ICUとCCU Volume: 44 Pages: 415-419
• [Journal Article] Fecal microbiota transplantation prevents Candida albicans from colonizing the gastrointestinal tract (2019)
  • Author(s): Matsuo K, Haku A, Bi B, Takahashi H, Kamada N, Yaguchi T, Saijo S, Yoneyama M, Goto Y.
  • Journal Title: Microbiology and Immunology Volume: - Issue: 5 Pages: 155-163
  • DOI: 10.1111/1348-0421.12680
  • NAID: 40021927492
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Fucosyltransferase 2 induces lung epithelial fucosylation and exacerbates house dust mite-induced airway inflammation. (2019)
  • Author(s): Saku A, Hirose K, Ito T, Iwata A, Sato T, Kaji H, Tamachi T, Suto A, Goto Y, Domino SE, Narimatsu H, Kiyono H, Nakajima H
  • Journal Title: J Allergy Clin Immunol. Volume: 144(3) Issue: 3 Pages: 698-709
  • DOI: 10.1016/j.jaci.2019.05.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Antigen-Specific Mucosal Immunity Regulates Development of Intestinal Bacteria-Mediated Diseases (2019)
  • Author(s): Fujimoto Kosuke、Kawaguchi Yunosuke、Shimohigoshi Masaki、Gotoh Yoshiyuki、Nakano Yoshiko、Usui Yuki、Hayashi Tetsuya、Kimura Yasumasa、Uematsu Miho、Yamamoto Takuya、Akeda Yukihiro、Rhee Joon Haeng、Yuki Yoshikazu、Ishii Ken J.、Crowe Sheila E.、Ernst Peter B.、Kiyono Hiroshi、Uematsu Satoshi
  • Journal Title: Gastroenterology Volume: 157 Issue: 6 Pages: 1530-1543
  • DOI: 10.1053/j.gastro.2019.08.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epithelial Cells as a Transmitter of Signals From Commensal Bacteria and Host Immune Cells (2019)
  • Author(s): Goto Y
  • Journal Title: Front Immunol Volume: 10 Pages: 2057-2057
  • DOI: 10.3389/fimmu.2019.02057
  • Peer Reviewed / Open Access
• [Journal Article] CD103hi Treg cells constrain lung fibrosis induced by CD103lo tissue-resident pathogenic CD4 T cells (2019)
  • Author(s): Ichikawa, T.*, Hirahara, K.*, Kokubo, K.*, Kiuchi, M., Aoki, A., Morimoto, Y., Kumagai, J., Onodera, A., Mato, N., Tumes, D., Goto, Y., Hagiwara, K., Inagaki, Y., Sparwasser, T., Tobe, K., and Nakayama, T.
  • Journal Title: Nature Immunology Volume: 20 Issue: 11 Pages: 1469-1480
  • DOI: 10.1038/s41590-019-0494-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Persistent colonization of non-lymphoid tissue-resident macrophages by Stenotrophomonas maltophilia (2019)
  • Author(s): Takahashi Ichiro, Hosomi Koji, Nagatake Takahiro, Tobou Hirokazu, Yamamoto Daiki, Hayashi Ikue, Kurashima Yosuke, Sato Shintaro, Shibata Naoko, Goto Yoshiyuki, Maruyama Fumito, Nakagawa Ichiro, Kuwae Asaomi, Abe Akio, Kunisawa Jun, Kiyono Hiroshi
  • Journal Title: International Immunology Volume: 32 Issue: 2 Pages: 133-141
  • DOI: 10.1093/intimm/dxz071
  • NAID: 120006888456
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 腸内真菌と免疫応答 (2019)
  • Author(s): 後藤 義幸
  • Journal Title: アレルギーの臨床 Volume: 39 Pages: 25-28
• [Journal Article] 腸内細菌による腸管上皮細胞のalpha1, 2-フコース修飾制御 (2019)
  • Author(s): 後藤 義幸
  • Journal Title: アレルギー Volume: 68 Pages: 151-154
• [Journal Article] Innate lymphoid cells regulate intestinal epithelial cell glycosylation. (2014)
  • Author(s): Goto Y, Obata T, Kunisawa J, Sato S, Ivanov II, Lamichhane A, Takeyama N, Kamioka M, Sakamoto M, Matsuki T, Uematsu S, Akira S, Domino SE, Kulig P, Becher B, Renauld JC, Sasakawa C, Umesaki Y, Benno Y, Kiyono H
  • Journal Title: Science Volume: 345 Issue: 6202 Pages: 1254009-1254009
  • DOI: 10.1126/science.1254009
  • Peer Reviewed / Open Access
• [Presentation] 腸内微生物と宿主免疫システムの相互作用. (2022)
  • Author(s): 後藤 義幸
  • Organizer: 第5回長崎腸内細菌研究会
  • Invited
• [Presentation] 腸内微生物叢と宿主免疫システムの相互作用. (2021)
  • Author(s): 後藤 義幸
  • Organizer: 第45回日本リンパ学会総会特別セミナー
  • Invited
• [Presentation] Intestinal Th17 cells induced by commensal fungi prevent inflammatory bowel disease (2021)
  • Author(s): Yoshiyuki Goto
  • Organizer: 第50回日本免疫学会学術集会
  • Int'l Joint Research
• [Presentation] 腸管上皮糖鎖修飾機構と腸管恒常性制御. (2021)
  • Author(s): 後藤 義幸
  • Organizer: 生化学工業株式会社 Glycoforum.
  • Invited
• [Presentation] 腸内細菌叢と宿主免疫システムの相互作用 (2020)
  • Author(s): 後藤 義幸
  • Organizer: 第11回関東甲信越免疫不全研究会
  • Invited
• [Presentation] 腸内真菌と腸内細菌、宿主免疫細胞の相互作用 (2020)
  • Author(s): 後藤 義幸
  • Organizer: 第32回日本薬学会微生物シンポジウム
  • Invited
• [Presentation] Large peritoneal macrophage delivers Salmonella from the peritoneal cavity to the greater omentum (2020)
  • Author(s): 高屋 明子、田代 翔吾、横井 達成、後藤 義幸、高橋 志達、岡 健太郎、川島 博人、山本 友子
  • Organizer: 第93回日本細菌学会総会
  • Int'l Joint Research
• [Presentation] Na+輸送性V-ATPaseはバンコマイシン耐性腸球菌に対する新たな創薬標的である (2020)
  • Author(s): 清水 康輝、薬師寺 リカファビアナ、森山 克彦、後藤 義幸、村田 武士
  • Organizer: 第93回日本細菌学会総会
  • Int'l Joint Research
• [Presentation] 腸内細菌は腸管における真菌の定着を阻害する (2019)
  • Author(s): 後藤 義幸
  • Organizer: 第92回日本細菌学会総会
  • Int'l Joint Research / Invited
• [Presentation] 腸内細菌による病原性真菌の腸管定着阻害機構 (2019)
  • Author(s): 後藤 義幸
  • Organizer: 第299回JSBMセミナー
  • Invited
• [Presentation] 腸内細菌は腸管における病原性真菌の定着を阻害する (2019)
  • Author(s): 後藤 義幸
  • Organizer: 第84回日本インターフェロンサイトカイン学会学術集会
  • Invited
• [Presentation] Commensal bacteria prevent Candida albicans colonization in the gut (2019)
  • Author(s): 後藤 義幸
  • Organizer: First Chiba University-University of Toronto Workshop
  • Int'l Joint Research / Invited
• [Presentation] 粘膜免疫学研究の最前線 (2019)
  • Author(s): 後藤 義幸
  • Organizer: 第56回日本小児アレルギー学会学術集会
  • Int'l Joint Research / Invited
• [Presentation] 腸管における宿主と共生微生物の相互作用 (2019)
  • Author(s): 後藤 義幸
  • Organizer: AMEDシンポジウム2019
  • Invited
• [Book] 実験医学別冊 もっとよくわかる！腸内細菌叢 健康と疾患を司る”もう1つの臓器” (2019)
  • Author(s): 福田真嗣、平山和宏、後藤義幸、小田巻俊孝、鎌田信彦、木村郁夫、大谷直子、山下智也、境洋平、石川大、坂本光央、中村祐哉、山田拓司、金倫基
  • Total Pages: 146
  • Publisher: 羊土社
  • ISBN: 9784758122061
• [Remarks] 千葉大学真菌医学研究センター感染免疫分野微生物・免疫制御プロジェクト
  • URL: http://www.pf.chiba-u.ac.jp/project_symbiosis/index.html
• [Patent(Industrial Property Rights)] 糖鎖の検出方法および細菌叢の構成の検出方法 (2020)
  • Inventor(s): 清野 宏、後藤 義幸
  • Industrial Property Rights Holder: 清野 宏、後藤 義幸
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-023944
  • Filing Date: 2020