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Enterocytes are the major epithelial cell type facilitating nutrient sensing and uptake. However, the molecular regulators governing enterocytes have remained undefined. Here, we identify c-Maf as an enterocyte-specific transcription factor within the SI epithelium. c-Maf expression was determined by opposing Noggin\/BMP signals and overlapped with the zonated enrichment of nutrient transporters in the mid-villus region. Functionally, enterocytes required c-Maf to appropriately differentiate along the villus axis. Specifically, gene programs controlling carbohydrate and protein absorption were c-Maf\u2013dependent. Consequently, epithelial cell\u2013specific c-Maf deletion resulted in impaired enterocyte maturation and nutrient uptake, including defects in the adaptation to different nutrient availability. Concomitantly, intraepithelial lymphocytes were less abundant, while commensal epithelial cell\u2013attaching SFB overgrew in a c-Maf\u2013deficient environment, highlighting the close interdependence between the intestinal epithelium, immune system, and microbiota. Collectively, our data identified c-Maf as a key regulator of SI enterocyte differentiation and function, essential for nutrient, immune, and microbial homeostasis.<\/jats:p>","DOI":"10.1084\/jem.20220233","type":"journal-article","created":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T13:24:38Z","timestamp":1663593878000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Intestinal epithelial c-Maf expression determines enterocyte differentiation and nutrient uptake in mice"],"prefix":"10.1084","volume":"219","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4412-4227","authenticated-orcid":true,"given":"Catalina","family":"Cosovanu","sequence":"first","affiliation":[{"name":"Department of Microbiology, Infectious Diseases and Immunology, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5466-9541","authenticated-orcid":true,"given":"Philipp","family":"Resch","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Infectious Diseases and Immunology, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9330-1715","authenticated-orcid":true,"given":"Stefan","family":"Jordan","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Infectious Diseases and Immunology, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8822-2609","authenticated-orcid":true,"given":"Andrea","family":"Lehmann","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9535-7413","authenticated-orcid":true,"given":"Markus","family":"Ralser","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany 2"},{"name":"The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London, UK 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4441-2552","authenticated-orcid":true,"given":"Vadim","family":"Farztdinov","sequence":"additional","affiliation":[{"name":"Core Facility - High-Throughput Mass Spectrometry, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8900-4467","authenticated-orcid":true,"given":"Joachim","family":"Spranger","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany 5"},{"name":"German Centre for Cardiovascular Research, partner site Berlin, Berlin, Germany 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9792-3861","authenticated-orcid":true,"given":"Michael","family":"M\u00fclleder","sequence":"additional","affiliation":[{"name":"Core Facility - High-Throughput Mass Spectrometry, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6336-3939","authenticated-orcid":true,"given":"Sebastian","family":"Brachs","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany 5"},{"name":"German Centre for Cardiovascular Research, partner site Berlin, Berlin, Germany 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2202-1876","authenticated-orcid":true,"given":"Christian","family":"Neumann","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Infectious Diseases and Immunology, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2022,9,19]]},"reference":[{"key":"2022091913240792700_bib1","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.1038\/s41590-018-0200-5","article-title":"An immunoregulatory and tissue-residency program modulated by c-MAF in human TH17 cells","volume":"19","author":"Aschenbrenner","year":"2018","journal-title":"Nat. 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