LSD1 drives intestinal epithelial maturation and controls small intestinal immune cell composition independent of microbiota in a murine model

Alberto Díez-Sánchez (), Håvard T. Lindholm, Pia M. Vornewald, Jenny Ostrop, Rouan Yao, Andrew B. Single, Anne Marstad, Naveen Parmar, Tovah N. Shaw, Mara Martín-Alonso and Menno J. Oudhoff ()
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Alberto Díez-Sánchez: Norwegian University of Science and Technology
Håvard T. Lindholm: Norwegian University of Science and Technology
Pia M. Vornewald: Norwegian University of Science and Technology
Jenny Ostrop: Norwegian University of Science and Technology
Rouan Yao: Norwegian University of Science and Technology
Andrew B. Single: Norwegian University of Science and Technology
Anne Marstad: Norwegian University of Science and Technology
Naveen Parmar: Norwegian University of Science and Technology
Tovah N. Shaw: University of Edinburgh
Mara Martín-Alonso: Norwegian University of Science and Technology
Menno J. Oudhoff: Norwegian University of Science and Technology

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Postnatal development of the gastrointestinal tract involves the establishment of the commensal microbiota, the acquisition of immune tolerance via a balanced immune cell composition, and maturation of the intestinal epithelium. While studies have uncovered an interplay between the first two, less is known about the role of the maturing epithelium. Here we show that intestinal-epithelial intrinsic expression of lysine-specific demethylase 1A (LSD1) is necessary for the postnatal maturation of intestinal epithelium and maintenance of this developed state during adulthood. Using microbiota-depleted mice, we find plasma cells, innate lymphoid cells (ILCs), and a specific myeloid population to depend on LSD1-controlled epithelial maturation. We propose that LSD1 controls the expression of epithelial-derived chemokines, such as Cxcl16, and that this is a mode of action for this epithelial-immune cell interplay in local ILC2s but not ILC3s. Together, our findings suggest that the maturing epithelium plays a dominant role in regulating the local immune cell composition, thereby contributing to gut homeostasis.

Date: 2024
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DOI: 10.1038/s41467-024-47815-2

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