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 nbutyrate, suggesting that mucin O-glycans act as an endogenous fermentation substrate for nbutyrate 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.Inflammatory bowel diseases (IBDs), such as ulcerative colitis (UC) and Crohn's disease (CD), are recurrent inflammatory disorders caused by both genetic and environmental factors [1,2]. Accumulating evidence has demonstrated that abnormal gut microbial composition, termed dysbiosis, plays a role in the pathogenesis and/or exacerbation of IBD in Caucasian patients [3,4]. The gut microbiota of IBD patients is characterized by diminished microbial diversity alongside the underrepresentation of Firmicutes and overrepresentation of Proteobacteria [3,5-8]. These characteristics are evident in the gut microbiota of CD patients, and the severity of dysbiosis in rectal mucosa-associated microbiota correlates well with disease score [7]. Changes in gut microbiota composition are less obvious in UC patients that in CD patients, and their association with IBD pathogenesis has not yet been elucidated [6,8]. Animal experiments have demonstrated that the gut microbiota shapes the host intestinal immune system under physiological conditions by inducing the maturation of gut-associated lymphoid tissues and the differentiation of Th17 and regulatory T cells [9]. In contrast, the gut microbiota drives intestinal inflammation under dysbiosis [10,11]. Similarly, the transplantation of microbiota from CD patients into Il10deficient mice has...