title: Human Clostridium difficile infection: altered mucus production and composition.
abstract: The majority of antibiotic-induced diarrhea is caused by Clostridium difficile (C. difficile). Hospitalizations for C. difficile infection (CDI) have tripled in the last decade, emphasizing the need to better understand how the organism colonizes the intestine and maintain infection. The mucus provides an interface for bacterial-host interactions and changes in intestinal mucus have been linked host health. To assess mucus production and composition in healthy and CDI patients, the main mucins MUC1 and MUC2 and mucus oligosaccharides were examined. Compared with healthy subjects, CDI patients demonstrated decreased MUC2 with no changes in surface MUC1. Although MUC1 did not change at the level of the epithelia, MUC1 was the primary constituent of secreted mucus in CDI patients. CDI mucus also exhibited decreased N-acetylgalactosamine (GalNAc), increased N-acetylglucosamine (GlcNAc), and increased terminal galactose residues. Increased galactose in CDI specimens is of particular interest since terminal galactose sugars are known as C. difficile toxin A receptor in animals. In vitro, C. difficile is capable of metabolizing fucose, mannose, galactose, GlcNAc, and GalNAc for growth under healthy stool conditions (low Na(+) concentration, pH 6.0). Injection of C. difficile into human intestinal organoids (HIOs) demonstrated that C. difficile alone is sufficient to reduce MUC2 production but is not capable of altering host mucus oligosaccharide composition. We also demonstrate that C. difficile binds preferentially to mucus extracted from CDI patients compared with healthy subjects. Our results provide insight into a mechanism of C. difficile colonization and may provide novel target(s) for the development of alternative therapeutic agents.
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio;
authors.forename: Melinda A
authors.initials: MA
authors.lastname: Engevik
authors.affiliation: Department of Medicine Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio;
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Yacyshyn
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio;
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Engevik
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio;
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Animal Health and Biomedical Sciences, University Wisconsin, Madison, Wisconsin; and.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Darien
authors.affiliation: Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio;
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hassett
authors.affiliation: Department of Medicine Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio; Digestive Health Center of Cincinnati Children's Hospital, Cincinnati, Ohio.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Yacyshyn
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio; Digestive Health Center of Cincinnati Children's Hospital, Cincinnati, Ohio Roger.Worrell@uc.edu.
authors.forename: Roger T
authors.initials: RT
authors.lastname: Worrell
mesh_terms: D000116:Acetylgalactosamine / Q000378:metabolism; D000117:Acetylglucosamine / Q000378:metabolism; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D016360:Clostridioides difficile / Q000254:growth & development / Q000302:isolation & purification / Q000378:metabolism*; D003106:Colon / Q000378:metabolism* / Q000382:microbiology*; D004761:Enterocolitis, Pseudomembranous / Q000378:metabolism* / Q000382:microbiology*; D005243:Feces / Q000382:microbiology; D005260:Female; D005690:Galactose / Q000031:analogs & derivatives / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D018396:Mucin-1 / Q000378:metabolism; D055262:Mucin-2 / Q000378:metabolism; D009093:Mucus / Q000378:metabolism*; D009940:Organoids; D039904:Pluripotent Stem Cells / Q000378:metabolism / Q000382:microbiology
chemical_list: C060192:MUC1 protein, human; C524625:MUC2 protein, human; D018396:Mucin-1; D055262:Mucin-2; D000116:Acetylgalactosamine; D000117:Acetylglucosamine; D005690:Galactose
keywords: C. difficile; MUC1; MUC2; intestinal organoid; mucus oligosaccharides