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.
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
