The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis

Kentaro Miyamoto; Tomohisa Sujino; Yosuke Harada; Hiroshi Ashida; Yusuke Yoshimatsu; Yuki Yonemoto; Yasuhiro Nemoto; Michio Tomura; Hassan Melhem; Jan Hendrik Niess; Toshihiko Suzuki; Toru Suzuki; Shohei Suzuki; Yuzo Koda; Ryuichi Okamoto; Yohei Mikami; Toshiaki Teratani; Kenji F. Tanaka; Akihiko Yoshimura; Toshiro Sato; Takanori Kanai

doi:10.1016/j.celrep.2023.113005

The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis

Cell Rep. 2023 Aug 29;42(8):113005. doi: 10.1016/j.celrep.2023.113005. Epub 2023 Aug 16.

Authors

Kentaro Miyamoto¹, Tomohisa Sujino², Yosuke Harada³, Hiroshi Ashida⁴, Yusuke Yoshimatsu³, Yuki Yonemoto⁵, Yasuhiro Nemoto⁵, Michio Tomura⁶, Hassan Melhem⁷, Jan Hendrik Niess⁸, Toshihiko Suzuki⁹, Toru Suzuki¹⁰, Shohei Suzuki³, Yuzo Koda³, Ryuichi Okamoto⁵, Yohei Mikami³, Toshiaki Teratani³, Kenji F. Tanaka¹⁰, Akihiko Yoshimura¹¹, Toshiro Sato¹², Takanori Kanai¹³

Affiliations

¹ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Miyarisan Pharmaceutical Co., Ltd., Research Laboratory, 1-10-3, Kaminagazato, Kita-ku, Tokyo 114-0016, Japan.
² Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: tsujino1224@keio.jp.
³ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
⁴ Department of Bacterial Infection and Host Response, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Medical Mycology Research Center, Chiba University, 1-8-1, Inohana, Cyuo-ku, Chiba city, Chiba 260-8673, Japan.
⁵ Department of Gastroenterology and Hepatology, Tokyo Medical Dental University (TMDU), 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
⁶ Laboratory of Immunology, Faculty of Pharmacy, Osaka Otani University, 3-11-1 Nshikiorikita, Tondabayshi, Osaka, 584-8584, Japan.
⁷ Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
⁸ Department of Biomedicine, University of Basel, 4031 Basel, Switzerland; Clarunis-University Center for Gastrointestinal and Liver Diseases, University Hospital Basel, 4002 Basel, Switzerland.
⁹ Department of Bacterial Infection and Host Response, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
¹⁰ Division of Brain Sciences Institute for Advanced Medical Research, Keio University School of Medicne, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
¹¹ Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
¹² Department of Organoid Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
¹³ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; AMED-CREST, Japan Agency for Medical Research and Development, 1-7-1, Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan. Electronic address: takagast@z2.keio.jp.

PMID: 37590143
DOI: 10.1016/j.celrep.2023.113005

Abstract

The intricate interplay between gut microbes and the onset of experimental autoimmune encephalomyelitis (EAE) remains poorly understood. Here, we uncover remarkable similarities between CD4⁺ T cells in the spinal cord and their counterparts in the small intestine. Furthermore, we unveil a synergistic relationship between the microbiota, particularly enriched with the tryptophan metabolism gene EC:1.13.11.11, and intestinal cells. This symbiotic collaboration results in the biosynthesis of kynurenic acid (KYNA), which modulates the recruitment and aggregation of GPR35-positive macrophages. Subsequently, a robust T helper 17 (Th17) immune response is activated, ultimately triggering the onset of EAE. Conversely, modulating the KYNA-mediated GPR35 signaling in Cx3cr1⁺ macrophages leads to a remarkable amelioration of EAE. These findings shed light on the crucial role of microbial-derived tryptophan metabolites in regulating immune responses within extraintestinal tissues.

Keywords: CD4(+) T cells; CP: Immunology; CP: Microbiology; GPR35; encephalomyelitis; gut microbes; immune system; kynurenic acid; macrophages; multiple sclerosis; spinal cord; tryptophan metabolites.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Encephalitis*
Encephalomyelitis, Autoimmune, Experimental*
Gastrointestinal Microbiome*
Kynurenic Acid
Macrophages
Tryptophan

Substances

Kynurenic Acid
Tryptophan