Faculty Collaboration Database

Paneth cell defects in Crohn's disease patients promote dysbiosis. JCI Insight 2016 Jun 02;1(8):e86907

Date

10/05/2016

Pubmed ID

27699268

Pubmed Central ID

PMC5033844

DOI

10.1172/jci.insight.86907

Scopus ID

2-s2.0-85055598517 (requires institutional sign-in at Scopus site)   94 Citations

Abstract

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

FUNDING: 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).

Author List

Liu TC, Gurram B, Baldridge MT, Head R, Lam V, Luo C, Cao Y, Simpson P, Hayward M, Holtz ML, Bousounis P, Noe J, Lerner D, Cabrera J, Biank V, Stephens M, Huttenhower C, McGovern DP, Xavier RJ, Stappenbeck TS, Salzman NH

Authors

Diana Lerner MD Professor in the Pediatrics department at Medical College of Wisconsin
Joshua D. Noe MD Associate Dean, Professor in the Pediatrics department at Medical College of Wisconsin
Amy Y. Pan PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Nita H. Salzman MD, PhD Center Director, Professor in the Pediatrics department at Medical College of Wisconsin
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Child
Child, Preschool
Crohn Disease
Dysbiosis
Gastrointestinal Microbiome
Humans
Ileum
Intestinal Mucosa
Paneth Cells