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/IRE1b, a paralogue of the most evolutionarily conserved endoplasmic reticulum stress sensor ERN1/IRE1a. 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 wild type 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.

Goblet cells need some stress

“…The lower endonuclease activity for ERN2 absence of ERN2, the expression of Xbp1s was reduced and Xbp1 -/mice showed a phenotype similar to that of Ern2 -/mice, proving that Xbp1 splicing induced by ERN2 was required for normal goblet cell function. Effects of the microbiota on the amount of Xbp1 have also been observed in other studies (10,13).…”

“…In this issue of the JCI, Grey and coauthors have continued to explore the function of ERN2 by using experimental animals (10). They nicely showed that Ern2-knockout mice had increased colon cell proliferation and elongated crypts as signs of mild spontaneous inflammation, which is similar to previous observations in Muc2-deficient mice (11).…”

“…This process was mediated by the goblet cell-specific ERN2 protein acting on Xbp1. Both ERN2 and ERN1 mediated Xbp1 splicing (10). While ERN2 and ERN1 acted in the same pathway, they were not redundant to each other, indicating that other functions must exist, a conundrum to be studied further.…”

“…The study by Grey et al (10) shows that forming mature goblet cells capable of producing sufficient amounts of mucus requires a baseline level of UPR with increased levels of chaperones and ER expansion. This process was mediated by the goblet cell-specific ERN2 protein acting on Xbp1.…”

Galactooligosaccharides ameliorate dietary advanced glycation end product-induced intestinal barrier damage in C57BL/6 mice by modulation of the intestinal microbiome

“…Consistently, Grey et al showed that the gut microbiota determined the ERN2 expression, further inducing the maturation of goblet cells and the assembly of the mucus barrier. 13 Inconsistent with donor mice, there were no significant differences in the gene transcription levels of occludin, claudin-1, claudin-2, and ZO-1 among the three groups of recipient mice. Note that Snelson et al found that consumption of a heat-treated diet for 24 weeks resulted in increased intestinal permeability in rats (reversed by AGE inhibitors).…”