Paneth cell defects in Crohn’s disease patients promote dysbiosis
Ta-Chiang Liu, … , Thaddeus S. Stappenbeck, Nita H. Salzman
Ta-Chiang Liu, … , Thaddeus S. Stappenbeck, Nita H. Salzman
Published June 2, 2016
Citation Information: JCI Insight. 2016;1(8):e86907. https://doi.org/10.1172/jci.insight.86907.
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Clinical Medicine Gastroenterology Microbiology

Paneth cell defects in Crohn’s disease patients promote dysbiosis

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).

Authors

Ta-Chiang Liu, Bhaskar Gurram, Megan T. Baldridge, Richard Head, Vy Lam, Chengwei Luo, Yumei Cao, Pippa Simpson, Michael Hayward, Mary L. Holtz, Pavlos Bousounis, Joshua Noe, Diana Lerner, Jose Cabrera, Vincent Biank, Michael Stephens, Curtis Huttenhower, Dermot P.B. McGovern, Ramnik J. Xavier, Thaddeus S. Stappenbeck, Nita H. Salzman

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Figure 2

The mucosal microbiome of pediatric Crohn’s disease (CD) (n = 36) and noninflammatory bowel disease (non-IBD) (n = 47) patients (Milwaukee cohort).

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The mucosal microbiome of pediatric Crohn’s disease (CD) (n = 36) and no...
(A and B) Alpha diversity of mucosal microbial composition in pediatric CD and non-IBD patients. Shown here with Shannon diversity index (A) (P = 0.1106, Mann-Whitney test) and Faith’s phylogenetic diversity index (B) (P = 0.0241, Mann-Whitney test). (C and D) Unweighted (C) (Kruskal-Wallis test P < 0.0001, Dunn’s multiple comparisons test P < 0.0001) and weighted (D) (Kruskal-Wallis test P = 0.0011, Dunn’s multiple comparisons test P < 0.01) beta diversity comparison within and between each group (Milwaukee cohort). *P < 0.05; ****P < 0.0001. Boxes extend from the 25th to 75th percentiles. The whiskers were plotted from the minimum to the maximum value, with each individual value as a dot on the graph. There was no outlying value that was not shown.