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Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis.

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.

SUBMITTER: Yamada T

PROVIDER: S-EPMC6838389 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis.

Yamada Takahiro T Hino Shingo S Iijima Hideki H Genda Tomomi T Aoki Ryo R Nagata Ryuji R Han Kyu-Ho KH Hirota Masato M Kinashi Yusuke Y Oguchi Hiroyuki H Suda Wataru W Furusawa Yukihiro Y Fujimura Yumiko Y Kunisawa Jun J Hattori Masahira M Fukushima Michihiro M Morita Tatsuya T Hase Koji K

EBioMedicine 20190911

<h4>Background</h4>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.<h4>Methods</h4>To elucidate relationships among dysbiosis, abnormal mucin utilisation, and microbial metabolic dysfunction, we analysed short-chain fatty acids (SCFAs) and mucin components i ...[more]

PMID: 31521614

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Project description:The gut microbiota is an integral part of the host and has a functional potential in host physiology. Numerous scientific efforts have opened new horizons in gut microbiota research and enhanced the understanding of host-microbe interactions in vertebrates. However, evidence on the association between the gut microbiota and immunity in invertebrates, especially in shrimp, which is an important aquatic animal, is limited. Herein, we conducted a comprehensive analysis based on 16S rRNA gene sequencing and liquid chromatography-coupled mass spectrometry (LC-MS) to investigate the correlation between them. Comparing the gut microbiota among the four different species of shrimp, we found huge variations and determined a core gut microbiota composed of 55 microbes. The environmental challenge of white spot syndrome virus (WSSV) infection led to changes in core microbial structures, but the alteration of core microbiota among different shrimp followed the same trend and showed immune-related function in the prediction of its metabolic potential. In metabolomic analysis, nine significantly upregulated metabolites found after viral infection indicated that they have antiviral potential. Moreover, we found a tight correlation between them and almost half of the core microbiota. These data demonstrate that these metabolites are responsible for maintaining the immune homeostasis of the host and prove the function of the gut microbiota and the related metabolome in antiviral immunity of shrimp. IMPORTANCE Abundant gut microorganisms constitute a complex microecosystem with the intestinal environment of the host, which plays a critical role in the adjustment of various physiological states of the organism. Sequencing and mass spectrometry data collected from intestinal samples of shrimp after virus infection helped to investigate the special function of the microecosystem and suggested that the gut microbiota has a functional potential in maintaining immune homeostasis of the host under environmental challenge.

Project description:BackgroundPost-weaning diarrhea in piglets reduces growth performance and increases mortality, thereby causing serious economic losses. The intestinal epithelial cells and microbiota reciprocally regulate each other in order to maintain intestinal homeostasis and control inflammation. However, a relative paucity of research has been focused on the host-derived regulatory network that controls mucin O-glycans and thereby changes gut microbiota during diarrhea in infancy. At the development stage just after birth, the ontogeny of intestinal epithelium, immune system, and gut microbiota appear similar in piglets and human infants. Here, we investigated the changes of mucin O-glycans associated with gut microbiota using a diarrheal post-weaned piglet model.ResultsWe found that diarrhea disrupted the colonic mucus layer and caused aberrant mucin O-glycans, including reduced acidic glycans and truncated glycans, leading to an impaired gut microenvironment. Subsequently, the onset of diarrhea, changes in microbiota and bacterial translocation, resulting in compromised epithelial barrier integrity, enhanced susceptibility to inflammation, and mild growth faltering. Furthermore, we found the activation of NLRP3 inflammasome complexes in the diarrheal piglets when compared to the healthy counterparts, triggered the release of proinflammatory cytokines IL-1β and IL-18, and diminished autophagosome formation, specifically the defective conversion of LC3A/B I into LC3A/B II and the accumulation of p62. Additionally, selective blocking of the autophagy pathway by 3-MA led to the reduction in goblet cell-specific gene transcript levels in vitro.ConclusionsWe observed that diarrheal piglets exhibited colonic microbiota dysbiosis and mucosal barrier dysfunction. Our data demonstrated that diarrhea resulted in the activation of inflammasomes and autophagy restriction along with aberrant mucin O-glycans including reduced acidic glycans and truncated glycans. The results suggested the mucin O-glycans-microbiota axis is likely associated with diarrheal pathogenesis. Our study provides novel insights into the pathophysiology of early-weaning-induced diarrheal disease in piglets and potentially understanding of disease mechanisms of diarrhea for human infants. Understanding the molecular pathology and pathogenesis of diarrhea is a prerequisite for the development of novel and effective therapies. Our data suggest that facilitating O-glycan elongation, modifying the microbiota, and developing specific inhibitors to some key inflammasomes could be the options for therapy of diarrhea including human infants. Video abstract.

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Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis.

Publications

Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis.

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