MUC17 is an essential small intestinal glycocalyx component that is disrupted in Crohn’s disease
Elena Layunta, Sofia Jäverfelt, Fleur C. van de Koolwijk, Molly Sivertsson, Brendan Dolan, Liisa Arike, Sara I.M. Thulin, Bruce A. Vallance, Thaher Pelaseyed
Elena Layunta, Sofia Jäverfelt, Fleur C. van de Koolwijk, Molly Sivertsson, Brendan Dolan, Liisa Arike, Sara I.M. Thulin, Bruce A. Vallance, Thaher Pelaseyed
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Research Article Cell biology Gastroenterology

MUC17 is an essential small intestinal glycocalyx component that is disrupted in Crohn’s disease

Abstract

Crohn’s disease (CD) is the chronic inflammation of the terminal ileum and colon triggered by a dysregulated immune response to bacteria, but insights into specific molecular perturbations at the critical bacteria-epithelium interface are limited. Here, we report that the membrane mucin MUC17 protected small intestinal enterocytes against commensal and pathogenic bacteria. In noninflamed CD ileum, reduced MUC17 levels and a compromised glycocalyx barrier allowed recurrent bacterial contact with enterocytes. Muc17 deletion in mice rendered the small intestine particularly prone to atypical bacterial infection while maintaining resistance to colitis. The loss of Muc17 resulted in spontaneous deterioration of epithelial homeostasis and in the extraintestinal translocation of bacteria. Finally, Muc17-deficient mice harbored specific small intestinal bacterial taxa observed in patients with CD. Our findings highlight MUC17 as an essential region-specific line of defense in the small intestine with relevance for early epithelial defects in CD.

Authors

Elena Layunta, Sofia Jäverfelt, Fleur C. van de Koolwijk, Molly Sivertsson, Brendan Dolan, Liisa Arike, Sara I.M. Thulin, Bruce A. Vallance, Thaher Pelaseyed

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Figure 5

Deletion of Muc17 results in alterations in luminal microbiota composition and translocation of commensal bacteria to peripheral tissues.

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Deletion of Muc17 results in alterations in luminal microbiota compositi...
(A) The α-diversity (Shannon index) of luminal bacterial communities in the Si of Muc17fl/fl (n = 11) and Muc17ΔIEC (n = 8) mice. (B) Principal coordinate analysis of β-diversity (Bray-Curtis dissimilarity) of luminal bacterial communities of Muc17fl/fl and Muc17ΔIEC Si. (C) Relative frequency of major classes found in Muc17fl/fl and Muc17ΔIEC Si. (D) The α-diversity (Shannon index) of luminal bacterial communities in the colon of Muc17fl/fl (n = 15) and Muc17ΔIEC (n = 13) mice. (E) Principal coordinate analysis of β-diversity (Bray-Curtis dissimilarity) of luminal bacterial communities in Muc17fl/fl and Muc17ΔIEC colon. (F) Relative frequency of major classes found in Muc17fl/fl and Muc17ΔIEC colon. (G) Linear discriminant analysis (LDA) effect size identification of small intestinal and colonic taxa that differentiate between Muc17fl/fl (blue) and Muc17ΔIEC (orange) mice. The heatmap shows the row z-score representing the relative abundance of the selected taxa in different gastrointestinal segments. Stom, stomach; Duo, duodenum; Si5, jejunum; Si8, ileum; Ce, cecum; C, colon; F, feces; ND, not detected. (H) Total weight of cohoused Muc17fl/fl (n = 19) and Muc17ΔIEC (n = 13) littermate mice. Box plots show the median and minimum to maximum values for each group. (I) Representative image of the opened abdomen of 36- to 40-week-old Muc17fl/fl and Muc17ΔIEC mice. Scale bar, 1 cm. (J) Quantification of bacterial 16S copy number in MLNs, spleen, and liver tissue by quantitative PCR. n = 5 for each group. (K) Quantification of bacterial growth in tissue homogenates of MLNs and spleen on BHIS agar plates under anaerobic conditions. (L) Representative image of bacterial growth in tissue homogenates of MLNs on BHIS agar under anaerobic conditions. (M) Identification of isolated bacterial colonies identified by 16S rRNA sequencing. Significance was determined by unpaired 2-tailed t test (A) and Mann-Whitney test (C).