2020/06/12
Keio University School of Medicine
Japan Agency for Medical Research and Development
A research group led by Professor Takanori Kanai, Project Lecturer Toshiaki Teratani, and Assistant Professor Yohei Mikami of the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, in collaboration with Professor Yuko Kitagawa of the Department of Surgery (General and Gastroenterological), Professor Hideyuki Okano of the Department of Physiology, Professor Akihiko Yoshimura of the Department of Microbiology and Immunology at the same university, Professor Yusaku Iwasaki of Kyoto Prefectural University, Professor Makoto Tsuda of Kyushu University, Associate Professor Mamoru Tanida of Kanazawa Medical University, Team Leader Mineyo Okada of RIKEN, Professor Shohei Hattori of the Faculty of Science and Technology, Waseda University (at the time of the research), and Professor Masayuki Inoue of the University of Tokyo, has revealed for the first time in the world that a mechanism exists in the body that integrates gut microbiota information from the intestinal tract in the liver, transmits it to the brain, and regulates the production of peripherally induced regulatory T cells (pTregs) in the intestine through a vagus nerve reflex.
In this study, the group revealed that antigen-presenting cells (APCs), which are crucial for the differentiation and maintenance of pTregs, are abundant near nerves in the intestinal lamina propria in mice. They also identified a neurotransmitter receptor highly expressed in intestinal APCs. When mouse and human APCs were stimulated with the antigen for this receptor, the expression of genes involved in pTreg differentiation and induction was enhanced, demonstrating a mechanism where signals from nerves in the intestinal lamina propria are received via intestinal APCs to suppress intestinal immunity. Furthermore, they found that artificially blocking the left vagus nerve from the liver to the brainstem in mice impaired the gene expression enhanced via intestinal APCs, leading to a significant decrease in the amount of pTregs. As a result, it was found that the pathology worsened in a mouse model of enteritis. These results indicate that the "gut-liver-brain-gut axis-mediated vagus nerve reflex" adjusts the amount of pTregs and maintains intestinal homeostasis.
This discovery is expected to lead to the elucidation of the pathological mechanisms and the development of new treatments for various diseases, including modern diseases caused by changes in the gut environment (such as inflammatory bowel disease, metabolic syndrome, and depression), cancer, and gastrointestinal infectious diseases including COVID-19.
The details of this research were published in the online edition of the British scientific journal "Nature" on June 11, 2020 (UK time).
For the full press release, please see below.