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The intestinal epithelium suffers constant challenges to the proteostasis machinery due to its exposure to the dynamically changing and microbial laden lumenal gut environment and to the high secretory demand placed on multiple epithelial cell types to accommodate gut and systemic physiology\u2014especially goblet, enteroendocrine and Paneth cells. In all cases, intestinal cells require an active unfolded protein response (UPR) to sustain their physiological function, the main pathway that monitors and adjusts secretory function changes in the environment. A specialised endoplasmic reticulum (ER) stress sensor uniquely expressed in epithelial cells lining mucosal surfaces, termed inositol-requiring transmembrane kinase\/endoribonuclease \u03b2, has specific roles in intestinal epithelial homeostasis, regulating mucus production and communication with microbiota. Chronic ER stress or genetic mutations affecting key UPR mediators contribute to the occurrence of inflammatory bowel disease and ulcerative colitis, in addition to colon cancer. Here, we review recent advances linking the UPR and ER stress with gut physiology and intestinal disease. Therapeutic strategies to alleviate ER stress or enforce UPR function to improve intestinal function in ageing and in bowel diseases are also discussed.<\/jats:p>","DOI":"10.1136\/egastro-2024-100129","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T07:55:12Z","timestamp":1735631712000},"page":"e100129","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Essential roles of the unfolded protein response in intestinal physiology"],"prefix":"10.1136","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1120-7966","authenticated-orcid":false,"given":"Claudio","family":"Hetz","sequence":"first","affiliation":[{"name":"Buck Institute for Research on Aging, Novato, California, USA"},{"name":"Center for Geroscience, Santiago, Chile"},{"name":"University of Chile, Santiago de Chile, Chile"},{"name":"Institute of Biomedical Sciences, Santiago de Chile, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Francisco","family":"Silva-Ag\u00fcero","sequence":"additional","affiliation":[{"name":"Center for Geroscience, Santiago, Chile"},{"name":"University of Chile, Santiago de Chile, Chile"},{"name":"Institute of Biomedical Sciences, Santiago de Chile, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa M","family":"Ellerby","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging, Novato, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,12,31]]},"reference":[{"key":"2025081719102915000_2.4.e100129.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2018.04.002"},{"key":"2025081719102915000_2.4.e100129.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-022-00675-x"},{"key":"2025081719102915000_2.4.e100129.3","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/s12276-024-01179-1","article-title":"Intestinal stem cells: guardians of homeostasis in health and aging amid environmental challenges","volume":"56","author":"Choi","year":"2024","journal-title":"Exp Mol Med"},{"key":"2025081719102915000_2.4.e100129.4","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2017.01271","article-title":"Intestinal Epithelial Cell Endoplasmic Reticulum Stress and Inflammatory Bowel Disease Pathogenesis: An Update Review","volume":"8","author":"Ma","year":"2017","journal-title":"Front Immunol"},{"key":"2025081719102915000_2.4.e100129.5","doi-asserted-by":"crossref","first-page":"216678","DOI":"10.1016\/j.canlet.2024.216678","article-title":"ER stress and the unfolded protein response in gastrointestinal stem cells and carcinogenesis","volume":"587","author":"de Boer","year":"2024","journal-title":"Cancer Lett"},{"key":"2025081719102915000_2.4.e100129.6","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-013-0377-5"},{"key":"2025081719102915000_2.4.e100129.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-0250-z"},{"key":"2025081719102915000_2.4.e100129.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.03.025"},{"key":"2025081719102915000_2.4.e100129.9","doi-asserted-by":"crossref","unstructured":"Verjan Garcia N , Hong KU , Matoba N . 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