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

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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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Keywords

  • Butyrate
  • Inflammatory bowel disease
  • Microbiota
  • Mucin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yamada, T., Hino, S., Iijima, H., Genda, T., Aoki, R., Nagata, R., Han, K. H., Hirota, M., Kinashi, Y., Oguchi, H., Suda, W., Furusawa, Y., Fujimura, Y., Kunisawa, J., Hattori, M., Fukushima, M., Morita, T., & Hase, K. (Accepted/In press). Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis. EBioMedicine. https://doi.org/10.1016/j.ebiom.2019.09.008