The organs of many female animals are remodeled by reproduction. Using the mouse intestine, a striking and tractable model of organ resizing, we find that reproductive remodeling is anticipatory and distinct from diet- or microbiota-induced resizing. Reproductive remodeling involves partially irreversible elongation of the small intestine and fully reversible growth of its epithelial villi, associated with an expansion of isthmus progenitors and accelerated enterocyte migration. We identify induction of the SGLT3a transporter in a subset of enterocytes as an early reproductive hallmark. Electrophysiological and genetic interrogations indicate that SGLT3a does not sustain digestive functions or enterocyte health; rather, it detects protons and sodium to extrinsically support the expansion of adjacent Fgfbp1-positive isthmus progenitors, promoting villus growth. Our findings reveal unanticipated specificity to physiological organ remodeling. We suggest that organ- and state-specific growth programs could be leveraged to improve pregnancy outcomes or prevent maladaptive consequences of such growth.

Department of Metabolism Digestion and Reproduction Faculty of Medicine Imperial College London Du Cane Road London W12 0NN UK

Department of Molecular and Cellular Biology Harvard University Cambridge MA 02138 USA

Friedrich Miescher Institute for Biomedical Research Fabrikstrasse 24 4056 Basel Switzerland; ETH Zürich Department for Biosystems Science and Engineering Basel Switzerland

Institut de Génomique Fonctionnelle de Lyon Ecole Normale Supérieure de Lyon CNRS UMR5242 UCBL Lyon 1 69007 Lyon France

King's College London Wolfson Sensory Pain and Regeneration Centre Hodgkin Building Guy's Campus London SE1 1UL UK

Laboratory of Gnotobiology Institute of Microbiology of the Czech Academy of Sciences 54922 Novy Hradek Czech Republic

Molecular Cancer Research Center for Molecular Medicine University Medical Center Utrecht 3584 CG Utrecht the Netherlands

MRC Laboratory of Medical Sciences Hammersmith Hospital Campus Du Cane Road London W12 0NN UK

MRC Laboratory of Medical Sciences Hammersmith Hospital Campus Du Cane Road London W12 0NN UK; Institute of Clinical Sciences Faculty of Medicine Imperial College London Du Cane Road London W12 0NN UK

The Francis Crick Institute 1 Midland Road London NW1 1AT UK

The Francis Crick Institute 1 Midland Road London NW1 1AT UK; Institute of Clinical Sciences Faculty of Medicine Imperial College London Du Cane Road London W12 0NN UK

The Francis Crick Institute 1 Midland Road London NW1 1AT UK; MRC Laboratory of Medical Sciences Hammersmith Hospital Campus Du Cane Road London W12 0NN UK

The Francis Crick Institute 1 Midland Road London NW1 1AT UK; MRC Laboratory of Medical Sciences Hammersmith Hospital Campus Du Cane Road London W12 0NN UK; Institute of Clinical Sciences Faculty of Medicine Imperial College London Du Cane Road London W12 0NN UK

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Cell. 2025 May 15;188(10):2825-2828. doi: 10.1016/j.cell.2025.04.023. PubMed

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