title: Paneth cell defects in Crohn's disease patients promote dysbiosis.
abstract: Paneth cell dysfunction has been implicated in a subset of Crohn's disease (CD) patients. We previously stratified clinical outcomes of CD patients by using Paneth cell phenotypes, which we defined by the intracellular distribution of antimicrobial proteins. Animal studies suggest that Paneth cells shape the intestinal microbiome. However, it is unclear whether Paneth cell phenotypes alter the microbiome complexity in CD subjects. Therefore, we analyzed the correlation of Paneth cell phenotypes with mucosal microbiome composition and ileal RNA expression in pediatric CD and noninflammatory bowel disease (non-IBD) patients.
  
  
  
  Pediatric CD (n= 44) and non-IBD (n= 62) patients aged 4 to 18 were recruited prior to routine endoscopic biopsy. Ileal mucosal samples were analyzed for Paneth cell phenotypes, mucosal microbiome composition, and RNA transcriptome.
  
  
  
  The prevalence of abnormal Paneth cells was higher in pediatric versus adult CD cohorts. For pediatric CD patients, those with abnormal Paneth cells showed significant changes in their ileal mucosal microbiome, highlighted by reduced protective microbes and enriched proinflammatory microbes. Ileal transcriptome profiles showed reduced transcripts for genes that control oxidative phosphorylation in CD patients with abnormal Paneth cells. These transcriptional changes in turn were correlated with specific microbiome alterations. In non-IBD patients, a subset contained abnormal Paneth cells. However, this subset was not associated with alterations in the microbiome or host transcriptome.
  
  
  
  Paneth cell abnormalities in human subjects are associated with mucosal dysbiosis in the context of CD, and these changes are associated with alterations in oxidative phosphorylation, potentially in a feedback loop.
  
  
  
  The research was funded by Helmsley Charitable Trust (to T.S. Stappenbeck, R.J. Xavier, and D.P.B. McGovern), Crohn's and Colitis Foundation of America (to N.H. Salzman, T.S. Stappenbeck, R.J. Xavier, and C. Huttenhower), and Doris Duke Charitable Foundation grant 2014103 (to T.C. Liu).
authors.affiliation: Department of Pathology and Immunology, Washington University, Saint Louis, Missouri, USA.
authors.forename: Ta-Chiang
authors.initials: TC
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Gurram
authors.affiliation: Department of Pathology and Immunology, Washington University, Saint Louis, Missouri, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Baldridge
authors.affiliation: Genome Technology Access Center, Washington University, Saint Louis, Missouri, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Head
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Vy
authors.initials: V
authors.lastname: Lam
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Chengwei
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Pediatrics, Division of Quantitative Health Services, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Pediatrics, Division of Quantitative Health Services, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Pippa
authors.initials: P
authors.lastname: Simpson
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Hayward
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Holtz
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Pavlos
authors.initials: P
authors.lastname: Bousounis
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Noe
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Lerner
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Cabrera
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Biank
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Stephens
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Huttenhower
authors.affiliation: The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Dermot Pb
authors.initials: DP
authors.lastname: McGovern
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Department of Pathology and Immunology, Washington University, Saint Louis, Missouri, USA.
authors.forename: Thaddeus S
authors.initials: TS
authors.lastname: Stappenbeck
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Nita H
authors.initials: NH
authors.lastname: Salzman
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003424:Crohn Disease / Q000503:physiopathology*; D064806:Dysbiosis / Q000503:physiopathology*; D000069196:Gastrointestinal Microbiome; D006801:Humans; D007082:Ileum / Q000166:cytology; D007413:Intestinal Mucosa / Q000166:cytology; D019879:Paneth Cells / Q000473:pathology*