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However, the host-derived regulatory network that controls mucus secretion and thereby changes gut microbiota has not been well studied. Here, we identify that Forkhead box protein O1 (Foxo1) regulates mucus secretion by goblet cells and determines intestinal homeostasis. Loss of Foxo1 in intestinal epithelial cells (IECs) results in defects in goblet cell autophagy and mucus secretion, leading to an impaired gut microenvironment and dysbiosis. Subsequently, due to changes in microbiota and disruption in microbiome metabolites of short-chain fatty acids, Foxo1 deficiency results in altered organization of tight junction proteins and enhanced susceptibility to intestinal inflammation. Our study demonstrates that Foxo1 is crucial for IECs to establish commensalism and maintain intestinal barrier integrity by regulating goblet cell function.<\/jats:p>","DOI":"10.1084\/jem.20210324","type":"journal-article","created":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T02:21:50Z","timestamp":1625106110000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":62,"title":["Foxo1 controls gut homeostasis and commensalism by regulating mucus secretion"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8151-8351","authenticated-orcid":true,"given":"Zuojia","family":"Chen","sequence":"first","affiliation":[{"name":"Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women\u2019s Hospital, Boston, MA 1"},{"name":"Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0489-4270","authenticated-orcid":true,"given":"Jialie","family":"Luo","sequence":"additional","affiliation":[{"name":"Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7076-3332","authenticated-orcid":true,"given":"Jian","family":"Li","sequence":"additional","affiliation":[{"name":"Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2613-1140","authenticated-orcid":true,"given":"Girak","family":"Kim","sequence":"additional","affiliation":[{"name":"Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9772-2357","authenticated-orcid":true,"given":"Eric S.","family":"Chen","sequence":"additional","affiliation":[{"name":"Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women\u2019s Hospital, Boston, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6458-2490","authenticated-orcid":true,"given":"Sheng","family":"Xiao","sequence":"additional","affiliation":[{"name":"Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women\u2019s Hospital, Boston, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0267-4247","authenticated-orcid":true,"given":"Scott B.","family":"Snapper","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Boston Children\u2019s Hospital, Boston, MA 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7610-3426","authenticated-orcid":true,"given":"Bin","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Boston, MA 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5082-1857","authenticated-orcid":true,"given":"Dingding","family":"An","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Boston, MA 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9704-248X","authenticated-orcid":true,"given":"Richard S.","family":"Blumberg","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1479-9533","authenticated-orcid":true,"given":"Cheng-hui","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Mary M. and Sash A. 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