The epithelial-specific ER stress sensor ERN2/IRE1β enables host-microbiota crosstalk to affect colon goblet cell development
Michael J. Grey, … , Jerrold R. Turner, Wayne I. Lencer
Michael J. Grey, … , Jerrold R. Turner, Wayne I. Lencer
Published June 21, 2022
Citation Information: J Clin Invest. 2022;132(17):e153519. https://doi.org/10.1172/JCI153519.
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Research Article Gastroenterology

The epithelial-specific ER stress sensor ERN2/IRE1β enables host-microbiota crosstalk to affect colon goblet cell development

Abstract

Epithelial cells lining mucosal surfaces of the gastrointestinal and respiratory tracts uniquely express ERN2/IRE1β, a paralogue of the most evolutionarily conserved endoplasmic reticulum stress sensor, ERN1/IRE1α. How ERN2 functions at the host-environment interface and why a second paralogue evolved remain incompletely understood. Using conventionally raised and germ-free Ern2–/– mice, we found that ERN2 was required for microbiota-induced goblet cell maturation and mucus barrier assembly in the colon. This occurred only after colonization of the alimentary tract with normal gut microflora, which induced Ern2 expression. ERN2 acted by splicing Xbp1 mRNA to expand ER function and prevent ER stress in goblet cells. Although ERN1 can also splice Xbp1 mRNA, it did not act redundantly to ERN2 in this context. By regulating assembly of the colon mucus layer, ERN2 further shaped the composition of the gut microbiota. Mice lacking Ern2 had a dysbiotic microbial community that failed to induce goblet cell development and increased susceptibility to colitis when transferred into germ-free WT mice. These results show that ERN2 evolved at mucosal surfaces to mediate crosstalk between gut microbes and the colonic epithelium required for normal homeostasis and host defense.

Authors

Michael J. Grey, Heidi De Luca, Doyle V. Ward, Irini A.M. Kreulen, Katlynn Bugda Gwilt, Sage E. Foley, Jay R. Thiagarajah, Beth A. McCormick, Jerrold R. Turner, Wayne I. Lencer

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Figure 2

Gut microbes induce colon goblet cell development in an ERN2-dependent manner.

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Gut microbes induce colon goblet cell development in an ERN2-dependent m...
(A) Bar graph shows the number of AB+ cells in the upper half of crypts in the distal colon of WT and Ern2–/– under CONV conditions, GF conditions, and GF followed by colonization with gut microbes from CONV-WT donor mice (Colonized). Symbols represent the average value for an individual animal, and data are represented as mean ± SEM. Mean values were compared by 2-way ANOVA. Data for CONV mice is from Figure 1A. (B) Violin plot showing relative mRNA expression for goblet cell signature genes upregulated in CONV-WT mice compared with GF-WT mice. Relative expression for those same genes is plotted for Ern2–/– mice. (C) Bar graphs show relative mRNA expression in colon crypts from WT and Ern2–/– mice for select genes measured by qPCR. Symbols represent individual mice, and data are represented as mean ± SEM. Mean values were compared by 2-way ANOVA. (D) Scatter plot compares differential expression of goblet cell signature genes for CONV-WT versus GF-WT compared with COLONIZED-WT versus GF-WT. (E) Bar graph shows enrichment of differentially expressed goblet cell signature genes for COLONIZED-WT and COLONIZED-Ern2–/– mice compared with GF controls. The heatmap shows the relative expression of differentially expressed genes. The subset of the genes not differentially expressed (Padj > 0.01) in Ern2–/– mice is indicated. (F) Violin plot showing the relative mRNA expression of epithelial cell signature genes from colon crypts of GF-Ern2–/– mice compared with GF-WT mice. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.