title: Bacteriome and Mycobiome Interactions Underscore Microbial Dysbiosis in Familial Crohn's Disease.
abstract: Crohn's disease (CD) results from a complex interplay between host genetic factors and endogenous microbial communities. In the current study, we used Ion Torrent sequencing to characterize the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in patients with CD and their nondiseased first-degree relatives (NCDR) in 9 familial clusters living in northern France-Belgium and in healthy individuals from 4 families living in the same area (non-CD unrelated [NCDU]). Principal component, diversity, and abundance analyses were conducted, and CD-associated inter- and intrakingdom microbial correlations were determined. Significant microbial interactions were identified and validated using single- and mixed-species biofilms. CD and NCDR groups clustered together in the mycobiome but not in the bacteriome. Microbiotas of familial (CD and NCDR) samples were distinct from those of nonfamilial (NCDU) samples. The abundance of Serratia marcescens and Escherichia coli was elevated in CD patients, while that of beneficial bacteria was decreased. The abundance of the fungus Candida tropicalis was significantly higher in CD than in NCDR (P = 0.003) samples and positively correlated with levels of anti-Saccharomyces cerevisiae antibodies (ASCA). The abundance of C. tropicalis was positively correlated with S. marcescens and E. coli, suggesting that these organisms interact in the gut. The mass and thickness of triple-species (C. tropicalis plus S. marcescens plus E. coli) biofilm were significantly greater than those of single- and double-species biofilms. C. tropicalis biofilms comprised blastospores, while double- and triple-species biofilms were enriched in hyphae. S. marcescens used fimbriae to coaggregate or attach with C. tropicalis/E. coli, while E. coli was closely apposed with C. tropicalis Specific interkingdom microbial interactions may be key determinants in CD.
  
  
  
  Here, we characterized the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in multiplex families with CD and healthy relatives and defined the microbial interactions leading to dysbiosis in CD. We identified fungal (Candida tropicalis) and bacterial (Serratia marcescens and Escherichia coli) species that are associated with CD dysbiosis. Additionally, we found that the level of anti-Saccharomyces cerevisiae antibodies (ASCA; a known CD biomarker) was associated with the abundance of C. tropicalis We also identified positive interkingdom correlations between C. tropicalis, E. coli, and S. marcescens in CD patients and validated these correlations using in vitro biofilms. These results provide insight into the roles of bacteria and fungi in CD and may lead to the development of novel treatment approaches and diagnostic assays.
authors.affiliation: Inserm U995-Team 2, Université Lille 2, Faculté de Médecine H. Warembourg, Pôle Recherche, CHRU de Lille, Lille, France.
authors.forename: G
authors.initials: G
authors.lastname: Hoarau
authors.affiliation: Center for Medical Mycology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Mukherjee
authors.affiliation: Epimad Registry, Epidemiology Unit and LIRIC Inserm 995, Lille University and Hospital, Lille, France.
authors.forename: C
authors.initials: C
authors.lastname: Gower-Rousseau
authors.affiliation: Center for Medical Mycology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: C
authors.initials: C
authors.lastname: Hager
authors.affiliation: Center for Medical Mycology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chandra
authors.affiliation: Center for Medical Mycology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Retuerto
authors.affiliation: Inserm U995-Team 2, Université Lille 2, Faculté de Médecine H. Warembourg, Pôle Recherche, CHRU de Lille, Lille, France.
authors.forename: C
authors.initials: C
authors.lastname: Neut
authors.affiliation: Department of Gastroenterology, University Hospital Leuven, Leuven, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Vermeire
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: J
authors.initials: J
authors.lastname: Clemente
authors.affiliation: Epimad Registry, Epidemiology Unit and LIRIC Inserm 995, Lille University and Hospital, Lille, France Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Colombel
authors.affiliation: EM Core Facility, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: H
authors.initials: H
authors.lastname: Fujioka
authors.affiliation: Inserm U995-Team 2, Université Lille 2, Faculté de Médecine H. Warembourg, Pôle Recherche, CHRU de Lille, Lille, France.
authors.forename: D
authors.initials: D
authors.lastname: Poulain
authors.affiliation: Inserm U995-Team 2, Université Lille 2, Faculté de Médecine H. Warembourg, Pôle Recherche, CHRU de Lille, Lille, France bsendid@univ-lille2.fr Mahmoud.Ghannoum@case.edu.
authors.forename: B
authors.initials: B
authors.lastname: Sendid
authors.affiliation: Center for Medical Mycology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA bsendid@univ-lille2.fr Mahmoud.Ghannoum@case.edu.
authors.forename: M A
authors.initials: MA
authors.lastname: Ghannoum
mesh_terms: D000328:Adult; D018441:Biofilms / Q000254:growth & development; D041022:Candida tropicalis / Q000302:isolation & purification; D003424:Crohn Disease / Q000235:genetics / Q000382:microbiology*; D064806:Dysbiosis / Q000382:microbiology*; D004926:Escherichia coli / Q000302:isolation & purification; D005243:Feces / Q000382:microbiology; D005260:Female; D010861:Fimbriae, Bacterial; D005602:France; D000069196:Gastrointestinal Microbiome; D064368:Healthy Volunteers; D006801:Humans; D025301:Hyphae / Q000302:isolation & purification; D008297:Male; D056265:Microbial Interactions; D008875:Middle Aged; D000072761:Mycobiome; D012441:Saccharomyces cerevisiae / Q000276:immunology; D012706:Serratia marcescens / Q000302:isolation & purification