Paneth cell defects in Crohn’s disease patients promote dysbiosis
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
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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Clinical Research and Public Health 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 5

The ileal mucosa of pediatric Crohn’s disease (CD) patients (total n = 38 with sufficient RNA) with Type I Paneth cell phenotype is associated with reduced expression of genes involved in oxidative phosphorylation.

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The ileal mucosa of pediatric Crohn’s disease (CD) patients (total n = 3...
(A) Heat map based on hierarchical clustering (Pearson with complete linkage) of gene expression profiles of Type I (n = 21) and Type II (n = 17) Paneth CD patients. Blue and red indicate lower and higher levels of expression, respectively. The cluster region containing the oxidative phosphorylation genes is labeled. (B–D) Expression of selected nuclear-encoded oxidative phosphorylation genes is associated with Paneth cell phenotype in CD patients (n = 38) but not in non-IBD patients (n = 51 with sufficient RNA), including COX6B1 (B), ATP5J2 (C), and NDUFA8 (D). Data in B–D analyzed by 1-way ANOVA. (E) Expression level of the oxidative phosphorylation gene COX6A1 correlates with the percentage of normal Paneth cells (D0) by Pearson’s correlation test. (F) Selected bacterial taxa that are significantly more abundant in CD patients with high expression level of oxidative phosphorylation genes (Faecalibacterium, Actinomyces, Verrrucomicrobiaceae) identified by Differential Feature analysis (LEfSe). (G) Reduced abundance of Faecalibacterium in CD patients with low oxidative phosphorylation expression levels (by Mann-Whitney test). *P < 0.05; **P < 0.01. 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.