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We reveal a local intestinal intraepithelial lymphocyte (IEL)-GLP-1 receptor (GLP-1R) signaling network that controls mucosal immune responses. Glp1r expression was enriched in intestinal IEL preparations and copurified with markers of T\u03b1\u03b2 and T\u03b3\u03b4 IELs, the two main subsets of intestinal IELs. Exendin-4 increased cAMP accumulation in purified IELs and reduced the production of cytokines from activated IELs but not from splenocytes ex vivo. These actions were mimicked by forskolin, absent in IELs from Glp1r\u2212\/\u2212 mice, and attenuated by the GLP-1R agonist exendin (9-39) consistent with a GLP-1R\u2013dependent mechanism of action. Furthermore, Glp1r\u2212\/\u2212 mice exhibited dysregulated intestinal gene expression, an abnormal representation of microbial species in feces, and enhanced sensitivity to intestinal injury following administration of dextran sodium sulfate. Bone marrow transplantation using wild-type C57BL\/6 donors normalized expression of multiple genes regulating immune function and epithelial integrity in Glp1r\u2212\/\u2212 recipient mice, whereas acute exendin-4 administration robustly induced the expression of genes encoding cytokines and chemokines in normal and injured intestine. Taken together, these findings define a local enteroendocrine-IEL axis linking energy availability, host microbial responses, and mucosal integrity to the control of innate immunity.<\/jats:p>","DOI":"10.2337\/db14-1577","type":"journal-article","created":{"date-parts":[[2015,3,3]],"date-time":"2015-03-03T22:32:37Z","timestamp":1425421957000},"page":"2537-2549","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":265,"title":["GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R"],"prefix":"10.2337","volume":"64","author":[{"given":"Bernardo","family":"Yusta","sequence":"first","affiliation":[{"name":"Department of Medicine, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie L.","family":"Baggio","sequence":"additional","affiliation":[{"name":"Department of Medicine, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Koehler","sequence":"additional","affiliation":[{"name":"Department of Medicine, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianne","family":"Holland","sequence":"additional","affiliation":[{"name":"Department of Medicine, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiemin","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Medicine, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee J.","family":"Pinnell","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathene C.","family":"Johnson-Henry","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Yeung","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Surette","sequence":"additional","affiliation":[{"name":"Department of Medicine, Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.W. 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