Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasisResearch in context

Takahiro Yamada; Shingo Hino; Hideki Iijima; Tomomi Genda; Ryo Aoki; Ryuji Nagata; Kyu-Ho Han; Masato Hirota; Yusuke Kinashi; Hiroyuki Oguchi; Wataru Suda; Yukihiro Furusawa; Yumiko Fujimura; Jun Kunisawa; Masahira Hattori; Michihiro Fukushima; Tatsuya Morita; Koji Hase

EBioMedicine (Oct 2019)

Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasisResearch in context

Takahiro Yamada,
Shingo Hino,
Hideki Iijima,
Tomomi Genda,
Ryo Aoki,
Ryuji Nagata,
Kyu-Ho Han,
Masato Hirota,
Yusuke Kinashi,
Hiroyuki Oguchi,
Wataru Suda,
Yukihiro Furusawa,
Yumiko Fujimura,
Jun Kunisawa,
Masahira Hattori,
Michihiro Fukushima,
Tatsuya Morita,
Koji Hase

Affiliations

Takahiro Yamada: Division of Biochemistry, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan
Shingo Hino: Department of Applied Biological Chemistry, Graduate School of Agriculture, Shizuoka University, Shizuoka, Japan
Hideki Iijima: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
Tomomi Genda: Department of Applied Biological Chemistry, Graduate School of Agriculture, Shizuoka University, Shizuoka, Japan
Ryo Aoki: Division of Gastroenterology and Hepatology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan
Ryuji Nagata: Department of Food Science, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido, Japan
Kyu-Ho Han: Department of Food Science, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido, Japan
Masato Hirota: Division of Biochemistry, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan
Yusuke Kinashi: Division of Biochemistry, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan
Hiroyuki Oguchi: Division of Biochemistry, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan
Wataru Suda: Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan; Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
Yukihiro Furusawa: Department of Liberal Arts and Sciences, Toyama Prefectural University, Toyama, Japan
Yumiko Fujimura: Division of Biochemistry, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan
Jun Kunisawa: Laboratory of Vaccine Materials and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan; Department of Microbiology and Immunology, Kobe University Graduate School of Medicine, Hyogo, Japan; Graduate School of Medicine, Graduate School of Pharmaceutical Sciences, Graduate School of Dentistry, Osaka University, Osaka, Japan; International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo, Japan
Masahira Hattori: Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan; Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
Michihiro Fukushima: Department of Food Science, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido, Japan
Tatsuya Morita: Department of Applied Biological Chemistry, Graduate School of Agriculture, Shizuoka University, Shizuoka, Japan; Corresponding author.
Koji Hase: Division of Biochemistry, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan; International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo, Japan; Corresponding author at: Division of Biochemistry, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo 105-8512, Japan.

Journal volume & issue: Vol. 48
pp. 513 – 525

Abstract

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Background: The dysbiosis of gut microbiota has been implicated in the pathogenesis of inflammatory bowel diseases; however, the underlying mechanisms have not yet been elucidated. Heavily glycosylated mucin establishes a first-line barrier against pathogens and serves as a niche for microbial growth. Methods: To elucidate relationships among dysbiosis, abnormal mucin utilisation, and microbial metabolic dysfunction, we analysed short-chain fatty acids (SCFAs) and mucin components in stool samples of 40 healthy subjects, 49 ulcerative colitis (UC) patients, and 44 Crohn's disease (CD) patients from Japan. Findings: Levels of n-butyrate were significantly lower in stools of both CD and UC patients than in stools of healthy subjects. Correlation analysis identified seven bacterial species positively correlated with n-butyrate levels; the major n-butyrate producer, Faecalibacterium prausnitzii, was particularly underrepresented in CD patients, but not in UC patients. In UC patients, there were inverse correlations between mucin O-glycan levels and the production of SCFAs, such as n-butyrate, suggesting that mucin O-glycans serve as an endogenous fermentation substrate for n-butyrate production. Indeed, mucin-fed rodents exhibited enhanced n-butyrate production, leading to the expansion of RORgt+Treg cells and IgA-producing cells in colonic lamina propria. Microbial utilisation of mucin-associated O-glycans was significantly reduced in n-butyrate-deficient UC patients. Interpretation: Mucin O-glycans facilitate symbiosynthesis of n-butyrate by gut microbiota. Abnormal mucin utilisation may lead to reduced n-butyrate production in UC patients. Fund: Japan Society for the Promotion of Science, Health Labour Sciences Research Grant, AMED-Crest, AMED, Yakult Foundation, Keio Gijuku Academic Development Funds, The Aashi Grass Foundation, and The Canon Foundation. Keywords: Microbiota, Butyrate, Mucin, Inflammatory bowel disease

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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