Xenotransplanted human organoids identify transepithelial zinc transport as a key mediator of intestinal adaptation

Maame Efua S. Sampah, Hannah Moore, Raheel Ahmad, Johannes Duess, Peng Lu, Carla Lopez, Steve Steinway, Daniel Scheese, Zachariah Raouf, Koichi Tsuboi, Jeffrey Ding, Connor Caputo, Madison McFarland, William B. Fulton, Sanxia Wang, Meghan Wang, Thomas Prindle, Vered Gazit, Deborah C. Rubin, Samuel Alaish, Chhinder P. Sodhi () and David J. Hackam ()
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Maame Efua S. Sampah: Johns Hopkins University School of Medicine
Hannah Moore: Johns Hopkins University School of Medicine
Raheel Ahmad: Johns Hopkins University School of Medicine
Johannes Duess: Johns Hopkins University School of Medicine
Peng Lu: Johns Hopkins University School of Medicine
Carla Lopez: Johns Hopkins University School of Medicine
Steve Steinway: Johns Hopkins University School of Medicine
Daniel Scheese: Johns Hopkins University School of Medicine
Zachariah Raouf: Johns Hopkins University School of Medicine
Koichi Tsuboi: Johns Hopkins University School of Medicine
Jeffrey Ding: Johns Hopkins University School of Medicine
Connor Caputo: Johns Hopkins University School of Medicine
Madison McFarland: Johns Hopkins University School of Medicine
William B. Fulton: Johns Hopkins University School of Medicine
Sanxia Wang: Johns Hopkins University School of Medicine
Meghan Wang: Johns Hopkins University School of Medicine
Thomas Prindle: Johns Hopkins University School of Medicine
Vered Gazit: Washington University School of Medicine
Deborah C. Rubin: Washington University School of Medicine
Samuel Alaish: Johns Hopkins University School of Medicine
Chhinder P. Sodhi: Johns Hopkins University School of Medicine
David J. Hackam: Johns Hopkins University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Short bowel syndrome (SBS) leads to severe morbidity and mortality. Intestinal adaptation is crucial in improving outcomes. To understand the human gene pathways associated with adaptation, we perform single-cell transcriptomic analysis of human small intestinal organoids explanted from mice with experimental SBS. We show that transmembrane ion pathways, specifically the transepithelial zinc transport pathway genes SLC39A4 and SLC39A5, are upregulated in SBS. This discovery is corroborated by an external dataset, bulk RT-qPCR, and Western blots. Oral zinc supplementation is shown to improve survival and weight gain of SBS mice and increase the proliferation of intestinal crypt cells in vitro. Finally, we identify the upregulation of SLC39A5 and associated transcription factor KLF5 in biopsied intestinal tissue specimens from patients with SBS. Thus, we identify zinc supplementation as a potential therapy for SBS and describe a xenotransplantation model that provides a platform for discovery in other intestinal diseases.

Date: 2024
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DOI: 10.1038/s41467-024-52216-6

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