PT  - JOURNAL ARTICLE
AU  - Takahiro Yamada
AU  - Shingo Hino
AU  - Hideki Iijima
AU  - Tomomi Genda
AU  - Ryo Aoki
AU  - Ryuji Nagata
AU  - Ho Han
AU  - Masato Hirota
AU  - Yusuke Kinashi
AU  - Hiroyuki Oguchi
AU  - Wataru Suda
AU  - Yukihiro Furusawa
AU  - Yumiko Fujimura
AU  - Jun Kunisawa
AU  - Masahira Hattori
AU  - Michihiro Fukushima
AU  - Tatsuya Morita
AU  - Koji Hase
TI  - Mucin <em>O</em>-glycans facilitate symbiosynthesis to maintain gut immune homeostasis
AID  - 10.1101/655597
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 655597
4099  - http://biorxiv.org/content/early/2019/05/30/655597.short
4100  - http://biorxiv.org/content/early/2019/05/30/655597.full
AB  - The dysbiosis of gut microbiota has been implicated in the pathogenesis of inflammatory bowel diseases (IBDs); however, the underlying mechanisms have not yet been elucidated. Heavily glycosylated mucin not only establishes a first-line barrier against pathogens, but also serves as a niche for microbial growth. We hypothesized that dysbiosis may cause abnormal mucin utilization and microbial metabolic dysfunction. To test this hypothesis, we analyzed short-chain fatty acids (SCFAs) and mucin components in the stool samples of 40 healthy subjects, 49 ulcerative colitis (UC) patients, and 44 Crohn’s disease (CD) patients from Japan. The levels of n-butyrate were significantly lower in the stools of both the CD and UC patients than in those of the healthy subjects. Correlation analysis identified 7 bacterial species positively correlated with n-butyrate levels, among which 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 act 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 the colonic lamina propria. Importantly, the availability of mucin-associated O-glycans to the microbiota was significantly reduced in n-butyrate-deficient UC patients. Taken together, our findings highlight the biological significance of the symbiosynthesis pathway in the production of n-butyrate, which maintains gut immune homeostasis.CDCrohn’s diseaseDNAdeoxyribonucleic acidFDRfalse discovery rateHPLChigh performance liquid chromatographyIBDinflammatory bowel diseaseIgAimmunoglobulin AOTUoperational taxonomic unitPCRpolymerase chain reactionRSresistant starchRNAribonucleic acidrRNAribosomal RNASCFAshort chain fatty acidTreg cellregulatory T cellTristris(hydroxymethyl)aminomethaneUCulcerative colitis