(741.1) The Epithelial-Specific ER Stress Sensor IRE1β Enables Host-Microbiota Crosstalk to Affect Colon Goblet Cell Development

Poster Board Number: E321

Michael Grey (Boston Childrens Hospital, Harvard Medical School), Heidi De Luca (Boston Childrens Hospital), Beth McCormick (University of Massachusetts Chan Medical School), Jerrold Turner (Brigham and Womens Hospital, Harvard Medical School), Wayne Lencer (Boston Childrens Hospital, Harvard Medical School)

Epithelial cells lining mucosal surfaces of the gastrointestinal and respiratory tracts uniquely express IRE1β (Ern2), a paralogue of the most evolutionarily conserved endoplasmic reticulum stress sensor IRE1α. How IRE1β functions at the host-environment interface and why a second IRE1 paralogue evolved remain incompletely understood. Using conventionally raised and germ-free Ern2-/- mice, we found that IRE1β 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 IRE1β expression. IRE1β acted by splicing Xbp1 mRNA to expand ER function and prevent ER stress in goblet cells. Although IRE1α can also splice Xbp1 mRNA, it did not act redundantly to IRE1β in this context. By regulating assembly of the colon mucus layer, IRE1β further shaped the composition of the gut microbiota. Mice lacking IRE1β had a dysbiotic microbial community that failed to induce goblet cell development when transferred into germ-free wild type mice. These results show that IRE1β evolved at mucosal surfaces to mediate crosstalk between gut microbes and the colonic epithelium required for normal homeostasis and host defense.

Support or Funding Information

This work was supported by National Institutes of Health grants K01DK119414 (M.J.G.), R01DK048106 (M.J.G. and W.I.L), R01DK125407 (B.A.M.), R01DK061931 (J.R.Tu.), and  Harvard Digestive Disease Center P30DK034854 (W.I.L.).

This work was supported by National Institutes of Health grants K01DK119414 (M.J.G.), R01DK048106 (M.J.G. and W.I.L), R01DK125407 (B.A.M.), R01DK061931 (J.R.Tu.), andamp;nbsp; Harvard Digestive Disease Center P30DK034854 (W.I.L.).