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Although sugar substitutes are commonly used as food additives for their sweet taste and lower calorie content, there is limited experimental evidence regarding their potential to drive gut remodeling. In this study, we designed experimental models for short\u2010term consumption of erythritol, a natural sugar alcohol widely used as a sugar substitute, and investigated its effects on gut remodeling and the underlying mechanisms. Our findings indicate that erythritol consumption induces hyperplasia in tuft cells (TCs) and goblet cells (GCs), as well as enhances the activity of intestinal stem cells\u2013increases in expression levels of\n                    <jats:italic>leucine\u2010rich repeat containing G protein\u2010coupled receptor 5<\/jats:italic>\n                    (\n                    <jats:italic>Lgr5<\/jats:italic>\n                    ), the key intestinal stem cell marker, in the number of proliferating stem cells, and facilitation of their differentiation into villi cells\u2013while maintaining the number of\n                    <jats:italic>Lgr5<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+<\/jats:italic>\n                    <\/jats:sup>\n                    intestinal stem cells. Notably, the enhanced stem cell activity was observed even in\n                    <jats:italic>Trpm5<\/jats:italic>\n                    knockout mice, suggesting that it is mechanistically independent of TC hyperplasia. Instead, we demonstrated the functional involvement of the gut microbiota, as antibiotic treatment abolished this effect, and fecal material transfer from erythritol\u2010consumed mice replicated the enhancement of stem cell activity in recipient mice. Furthermore, we identified acetate as the metabolite responsible for enhancing stem cell activity. These findings suggest the functional decoupling of TC hyperplasia and the enhancement of stem cell activity, providing a potential therapeutic avenue for gut epithelial diseases.\n                  <\/jats:p>","DOI":"10.1096\/fj.202402105rr","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T08:14:01Z","timestamp":1738656841000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Dual independent mechanisms underlying gut epithelial remodeling upon sugar substitute consumption"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2208-7399","authenticated-orcid":false,"given":"Dong Woo","family":"Seo","sequence":"first","affiliation":[{"name":"Department of Pharmacology Korea University College of Medicine  Seoul Republic of Korea"},{"name":"BK21 Graduate Program, Department of Biomedical Sciences Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8914-0215","authenticated-orcid":false,"given":"Kyung Tae","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4274-2884","authenticated-orcid":false,"given":"Jung Hoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Korea University College of Medicine  Seoul Republic of Korea"},{"name":"BK21 Graduate Program, Department of Biomedical Sciences Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3641-1728","authenticated-orcid":false,"given":"Jun\u2010Seok","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Korea University College of Medicine  Seoul Republic of Korea"},{"name":"BK21 Graduate Program, Department of Biomedical Sciences Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0067-6396","authenticated-orcid":false,"given":"Yong Taek","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Korea University College of Medicine  Seoul Republic of Korea"},{"name":"BK21 Graduate Program, Department of Biomedical Sciences Korea University College of Medicine  Seoul Republic of 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