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Here, we aimed to determine the effect of Tff3 deficiency on intestinal tissues in a long-term high-fat-diet (HFD)-fed model. A novel congenic strain without additional metabolically relevant mutations (Tff3-\/-\/C57Bl6NCrl strain, male and female) was used. Wild type (Wt) and Tff3-deficient mice of both sexes were fed a HFD for 36 weeks. Long-term feeding of a HFD induces different effects on the intestinal structure of Tff3-deficient male and female mice. For the first time, we found sex-specific differences in duodenal morphology. HFD feeding reduced microvilli height in Tff3-deficient females compared to that in Wt females, suggesting a possible effect on microvillar actin filament dynamics. These changes could not be attributed to genes involved in ER and oxidative stress, apoptosis, or inflammation. Tff3-deficient males exhibited a reduced cecal crypt depth compared to that of Wt males, but this was not the case in females. Microbiome-related short-chain fatty acid content was not affected by Tff3 deficiency in HFD-fed male or female mice. Sex-related differences due to Tff3 deficiency imply the need to consider both sexes in future studies on the role of Tff in intestinal function.<\/jats:p>","DOI":"10.3390\/ijms242216342","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T10:51:37Z","timestamp":1700045497000},"page":"16342","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tff3 Deficiency Differentially Affects the Morphology of Male and Female Intestines in a Long-Term High-Fat-Diet-Fed Mouse Model"],"prefix":"10.3390","volume":"24","author":[{"given":"Kate","family":"\u0160e\u0161elja","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bjeni\u010dka 54, 10 000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iva","family":"Bazina","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bjeni\u010dka 54, 10 000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9968-9228","authenticated-orcid":false,"given":"Milka","family":"Vrecl","sequence":"additional","affiliation":[{"name":"Institute of Preclinical Sciences, Veterinary Faculty, University of Ljubljana, Gerbi\u010deva 60, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Farger","sequence":"additional","affiliation":[{"name":"Institute of Functional and Clinical Anatomy, Faculty of Medicine, Friedrich-Alexander-University Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5155-5477","authenticated-orcid":false,"given":"Martin","family":"Schicht","sequence":"additional","affiliation":[{"name":"Institute of Functional and Clinical Anatomy, Faculty of Medicine, Friedrich-Alexander-University Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0527-0953","authenticated-orcid":false,"given":"Friedrich","family":"Paulsen","sequence":"additional","affiliation":[{"name":"Institute of Functional and Clinical Anatomy, Faculty of Medicine, Friedrich-Alexander-University Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6940-2302","authenticated-orcid":false,"given":"Mirela","family":"Baus Lon\u010dar","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bjeni\u010dka 54, 10 000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7549-4488","authenticated-orcid":false,"given":"Tatjana","family":"Pirman","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Jamnikarjeva 101, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2956","DOI":"10.1007\/s00018-005-5484-6","article-title":"Structure of mammalian trefoil factors and functional insights","volume":"62","author":"Thim","year":"2005","journal-title":"Cell. 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