Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis

Abstract

BackgroundThe 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.MethodsTo 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.FindingsLevels 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.InterpretationMucin O-glycans facilitate symbiosynthesis of n-butyrate by gut microbiota. Abnormal mucin utilisation may lead to reduced n-butyrate production in UC patients.FundJapan 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.

Changes in dietary fiber intake in mice reveal associations between colonic mucin O-glycosylation and specific gut bacteria

“…This identified significant positive correlations between glycans terminating with Neu5Ac (N) and two SCFAs, acetate, and butyrate (Pearson correlation = 0.55 and 0.36, respectively). Colonic mucin O -glycans have been proposed to regulate the production of SCFAs, 47 , 48 specifically the biosynthesis of butyrate. 47 However, these previous studies were limited to quantifying the total mucin proteins and O -glycans.…”

“…Colonic mucin O -glycans have been proposed to regulate the production of SCFAs, 47 , 48 specifically the biosynthesis of butyrate. 47 However, these previous studies were limited to quantifying the total mucin proteins and O -glycans. Our study provides further insight and demonstrates an association between specific mucin O -glycan structures and the concentrations of acetate and butyrate.…”

Intestinal Flora and Disease Mutually Shape the Regional Immune System in the Intestinal Tract

“…In early life, appropriate intestinal colonization by specific microflora stimulates maturation of the intestinal mucosa-associated lymphoid tissue (6). Should the appropriate intestinal flora fail to form during this life stage, the function of the intestinal immune system becomes impaired, leading to increased incidence and/or morbidity of certain intestinal diseases, including ulcerative colitis, Crohn's disease, and colorectal cancer (7,8). In addition, activation of the immune system in the intestinal region depends on expression of pathogen-associated molecular patterns (PAMPs), e.g., intestinal microbial products.…”

Molecular Insights Into O-Linked Glycan Utilization by Gut Microbes

“…It is known that animals that are fed mucin show higher fecal butyrate levels. This compound is an anti-inflammatory SCFA considered positive for health and significantly decreased in inflammatory diseases such as Ulcerative Colitis (UC; Chen et al, 2018;Yamada et al, 2019). In UC subjects, mucin O-glycan abundance correlates negatively with butyrate production in feces, showing a reduced utilization of O-glycans by the gut microbiota (Yamada et al, 2019).…”

“…Yamada et al (2019) reported that fermentation of mucin O-glycans is associated with the production of butyrate in healthy subjects. However, subjects with UC show altered mucin O-glycosylation patterns, and the abundance of A. muciniphila was inversely proportional to the markers of inflammation (Earley et al, 2019;Yamada et al, 2019). This suggests that the O-glycosylation patterns present in mucins influence the anti-inflammatory activity of certain commensal microorganisms.…”