The epithelial-specific ER stress sensor ERN2/IRE1β enables host-microbiota crosstalk to affect colon goblet cell development
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
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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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 6

Ern2–/– microbiota are unable to support goblet cell development when transferred into WT recipient mice.

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Ern2–/– microbiota are unable to support goblet cell development when t...
Bar graphs show number of AB+ cells per crypt in the upper half of crypts in the distal colon of (A) GF-WT mice (n = 3) and GF-WT mice colonized with microbiota from WT (n = 9) or Ern2–/– (n = 8) donor mice and (B) CONV-WT mice (n = 11), antibiotic-treated CONV-WT mice (n = 11), and antibiotic-treated CONV-WT mice that were cohoused with WT (n = 9) or Ern2–/– (n = 7) donor mice. Symbols represent individual mice. Data are represented as mean ± SEM. Mean values were compared by 1-way ANOVA. (C) Bar graphs show relative mRNA expression for indicated genes measured by qPCR in colon epithelial cells from antibiotic-treated WT mice that were cohoused with either WT (n = 5) or Ern2–/– (n = 4) donor mice. Expression levels are shown relative to control WT mice (no antibiotics, no cohousing). (D) Time courses show (left panel) change in body weight and (right panel) survival during administration of DSS for 8 days followed by 14 days of recovery for WT (n = 6), Ern2–/– (n = 7), and antibiotic-treated WT mice cohoused with WT (n = 7) or Ern2–/– donors (n = 6). Survival curves were compared using log rank test. (E) Box plots show α diversity indices for microbiota from WT and Ern2–/– mice. Symbols represent values for individual mice, and error bars represent minimum and maximum. (F) Box plots show relative abundance data for indicated taxa that are significantly different between microbiota from CONV-WT and CONV-Ern2–/– mice. Symbols represent relative abundance for an individual mouse. FDR q values were calculated with MaAsLin2 (63) (WT, n = 14; Ern2–/–, n = 9). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.