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【科技部新聞稿】破解腸道與大腦的摩斯密碼,腸道細菌調控動物的壓力反應與社交行為 / Little friends in the gut control social behavior through stress hormone pathway

破解腸道與大腦的摩斯密碼

腸道細菌調控動物的壓力反應與社交行為

日期:110年7月14日

發稿單位:生命科學研究發展司

聯絡人:張友琪副研究員

電話:(02) 2737-7544

E-mail:yochang@most.gov.tw

科技部一直以來致力於輔助年輕學者追求學術卓越,在生命科學領域探究生命奧秘,進而創造科技突破造福人群。本次研究在科技部與成功大學合力支持之下,由成功大學醫學院生理學科暨研究所吳偉立助理教授研究團隊,與美國加州理工學院生物及生物工程學院 Sarkis Mazmanian 教授研究團隊透過國際合作,共同解開了腸道中的寄居細菌 (gut microbiota) 如何影響宿主社交行為之迷。本項研究成果榮登生命科學領域最頂尖期刊之一《自然 (Nature) 》 期刊,不僅受到國內外高度重視,更是將臺灣基礎科學研究實力推向國際的最佳典範。

社交行為對於人類與動物來說是一項提升生存、降低能量消耗、提供安全感的重要行為。社交行為缺損是自閉症、思覺失調症、憂鬱症、社交焦慮症等疾病的症狀之一。本研究證明了腸道共生細菌透過抑制壓力反應進而促進老鼠的社交行為,為前述疾病的治療開啟了一道新門窗。本研究首先證明完全無菌鼠 (germ-free mice; 全身都沒有任何共生細菌) 以及成年時期接受抗生素處理細菌後的老鼠,在面對同種個體時的社交互動行為表現量均較低;然而,其血液中的壓力賀爾蒙-皮質酮濃度則較高。研究團隊進一步利用藥物阻斷皮質酮訊息路徑,或是經由手術摘除腎上腺以阻斷產生皮質酮的主要來源時,發現降低壓力賀爾蒙-皮質酮可以恢復無菌鼠的社交行為。研究亦發現在腦部特定區域精準剔除皮質酮接受器-葡萄糖皮質素受體,或是利用化學遺傳學抑制促腎上線皮質激素釋放激素神經元(分泌皮質酮的上游路徑),皆可降低抗生素處理後小鼠的壓力賀爾蒙,以及增加小鼠的社交行為。相反的,在具有正常腸道共生細菌的小鼠身上,以化學遺傳學方式促進促腎上線皮質激素釋放激素神經元,或是直接刺激特定腦區壓力反應神經元,壓力增加後皆會造成小鼠社交行為缺損。最後研究團隊發現在抗生素處理過後的老鼠腸道中給予一種特定腸道細菌「糞腸球菌」,將可以降低其壓力賀爾蒙以及增加其社交行為,成功破解腸道與大腦的摩斯密碼,證實了腸道細菌調控動物的壓力反應與社交行為。未來團隊將持續投入系列研究,找出糞腸球菌究竟是透過何種方式或其代謝物質來影響宿主的壓力反應。

本研究由科技部經費支持,成功大學醫學院與高教深耕經費贊助;由吳偉立助理教授與美國Sarkis Mazmanian 教授共同主導,雙方研究團隊共同執行協力完成。論文唯一第一作者與責任作者為吳偉立助理教授,參與協助完成研究的台灣學生包括:成功大學基礎醫學所學生劉嘉瑋(第三作者)、成功大學生理所學生賴姿廷 (第五作者)、林元元 (第十二作者)、姚子宣 (第十三作者)等四位成功大學學生。本研究同時聯合加州理工學院 Rustem Ismagilov 教授及 Viviana Gradinaru 教授及其團隊的參與,跨國團隊合作成功地揭露腸道共生細菌在腸腦軸的角色以及調控宿主行為的路徑。

 

示意圖:腸道共生細菌在腸腦軸的角色以及調控宿主行為的路徑

 

研究成果聯絡人

吳偉立 博士 (Wei-Li Wu, PhD)

國立成功大學醫學院生理所 助理教授

聯絡電話(公):06-2353535 EXT 5458

電子郵件信箱:wlwu@ncku.edu.tw

 

 

Little friends in the gut control social behavior through stress hormone pathway

 

Gut feeling, an idiom widely used in western culture, describes an instinctive feeling but not knowing the exact reason. Now a team of National Cheng Kung University (NCKU) and California Institute of Technology (Caltech) scientists has explored how gut bacteria influence mouse social behavior through a distinct stress response pathway in the brain. The novel finding, discussed in an article published in the journal Nature on July 15, 2021, has solved a missing piece of the connection between the gut and the brain, the authors say.

 

Social interactions among animals mediate essential behaviors, including mating, nurturing, and defense. Social behavior provides benefits such as increases survival, offers security, reduces energy expenditure. The deficit in social interaction is often observed in people with psychiatric disorders, such as autism, schizophrenia, depression, social anxiety, etc. While the intestinal bacteria contribute to social behavior in mice, gut-brain connections that regulate this complex behavior and its underlying neural basis remain poorly understood. The NCKU-Caltech team reveals that the microbiota modulates neuronal activity in specific brain regions in male mice to regulate stress responses and social behavior. Social deficit in mice without gut bacteria is associated with elevated levels of the stress hormone corticosterone, which is primarily produced by activating the hypothalamus-pituitary-adrenal (HPA) axis, a well-known system for stress response. Accordingly, removal of the adrenal gland, blockade of the glucocorticoid receptor, and pharmacological inhibition of corticosterone synthesis effectively correct social deficits modulated by gut bacteria. Genetic deletion of the glucocorticoid receptor in specific brain regions and chemogenetic inactivation of corticotrophin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus of the hypothalamus (PVN) rescue social impairments caused by microbiome depletion. Conversely, specific activation of CRH-expressing neurons in the PVN of mice is sufficient to induce social deficits. Finally, the team identifies a specific bacterial species, Enterococcus faecalis, that promotes social activity and reduces stress hormone in mice following social stress. These discoveries demonstrate that the gut microbiome can modulate social interactions via specific neuronal circuits that control stress responses in the brain.

 

This study was partially supported by the Ministry of Science and Technology, College of Medicine, and Higher Education Sprout Project at NCKU, Taiwan. The research was conducted by Prof. Wei-Li Wu and his team in the Department of Physiology at NCKU in collaboration with the team led by Prof. Sarkis Mazmanian of the Division of Biology and Biological Engineering at Caltech.

Author Information:

 

Prof. Wei-Li Wu (the lead and corresponding author of this paper), assistant professor in the Department of Physiology, College of Medicine at NCKU and visiting associate in the Division of Biology and Biological Engineering at Caltech.

 

Prof. Sarkis Mazmanian, Luis B. and Nelly Soux Professor of Microbiology in the Division of Biology and Biological Engineering at Caltech, faculty member with Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech, and Heritage Medical Research Institute Investigator.

 

Underline: Authors from NCKU

Co-authors are Mark D. Adame, formerly of Caltech and now at the MD-PhD program of University of Michigan-Ann Arbor; PhD graduate student Chia-Wei Liou (third author) of Institute of Basic Biomedical Sciences, NCKU; graduate student Jacob T. Barlow of Caltech; MS graduate student Tzu-Ting Lai (fifth author) (MS '21); Gil Sharon formerly a postdoc at Caltech and now at the Emerald Cloud Lab; Catherine E. Schretter, formerly a graduate student at Caltech and now at the Janelia Research Campus; Postdoc Brittany D. Needham of Caltech; Madelyn I. Wang, formerly of Caltech and now at the MD program of Stony Brook University; graduate students Weiyi Tang and James Ousey of Caltech; MS graduate student Yuan-Yuan Lin (twelfth author) and BS undergraduate student Tzu-Hsuan Yao (thirteenth author) of Department of Physiology, NCKU; graduate student Reem Abdel-Haq of Caltech; Keith Beadle, formerly of Caltech and now at the Oregon Health and Science University; Professors Viviana Gradinaru and Rustem F. Ismagilov of Caltech; and Sarkis Mazmanian.

 

 

Research Contact

Prof. Wei-Li Wu, PhD

Department of Physiology, College of Medicine

National Cheng Kung University

TEL: +886-6-235-3535 ext 5458

Email: wlwu@ncku.edu.tw

 

 

Media Contact

Yo-Chi Chang

Program Manager

Department of Life Sciences

Ministry of Science and Technology

TEL: +886-2-2737-7544

Email: yochang@most.gov.tw

更新日期 : 2021/07/19