Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis

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, Kouji Hase

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalEBioMedicine
DOIs
Publication statusAccepted/In press - 2019 Jan 1

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Butyrates
Mucins
Polysaccharides
Homeostasis
Ulcerative Colitis
Dysbiosis
Crohn Disease
Volatile Fatty Acids
Healthy Volunteers
Japan
Pathogens
Financial Management
Regulatory T-Lymphocytes
Poaceae
Health Promotion
Inflammatory Bowel Diseases
Fermentation
Immunoglobulin A
Rodentia
Mucous Membrane

Keywords

  • Butyrate
  • Inflammatory bowel disease
  • Microbiota
  • Mucin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis. / Yamada, Takahiro; Hino, Shingo; Iijima, Hideki; Genda, Tomomi; Aoki, Ryo; Nagata, Ryuji; Han, Kyu Ho; Hirota, Masato; Kinashi, Yusuke; Oguchi, Hiroyuki; Suda, Wataru; Furusawa, Yukihiro; Fujimura, Yumiko; Kunisawa, Jun; Hattori, Masahira; Fukushima, Michihiro; Morita, Tatsuya; Hase, Kouji.

In: EBioMedicine, 01.01.2019.

Research output: Contribution to journalArticle

Yamada, T, Hino, S, Iijima, H, Genda, T, Aoki, R, Nagata, R, Han, KH, Hirota, M, Kinashi, Y, Oguchi, H, Suda, W, Furusawa, Y, Fujimura, Y, Kunisawa, J, Hattori, M, Fukushima, M, Morita, T & Hase, K 2019, 'Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis', EBioMedicine. https://doi.org/10.1016/j.ebiom.2019.09.008
Yamada, Takahiro ; Hino, Shingo ; Iijima, Hideki ; Genda, Tomomi ; Aoki, Ryo ; Nagata, Ryuji ; Han, Kyu Ho ; Hirota, Masato ; Kinashi, Yusuke ; Oguchi, Hiroyuki ; Suda, Wataru ; Furusawa, Yukihiro ; Fujimura, Yumiko ; Kunisawa, Jun ; Hattori, Masahira ; Fukushima, Michihiro ; Morita, Tatsuya ; Hase, Kouji. / Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis. In: EBioMedicine. 2019.
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AU - Iijima, Hideki

AU - Genda, Tomomi

AU - Aoki, Ryo

AU - Nagata, Ryuji

AU - Han, Kyu Ho

AU - Hirota, Masato

AU - Kinashi, Yusuke

AU - Oguchi, Hiroyuki

AU - Suda, Wataru

AU - Furusawa, Yukihiro

AU - Fujimura, Yumiko

AU - Kunisawa, Jun

AU - Hattori, Masahira

AU - Fukushima, Michihiro

AU - Morita, Tatsuya

AU - Hase, Kouji

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N2 - 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.

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