TY - JOUR
T1 - Xenotransplanted human organoids identify transepithelial zinc transport as a key mediator of intestinal adaptation
AU - Sampah, Maame Efua S.
AU - Moore, Hannah
AU - Ahmad, Raheel
AU - Duess, Johannes
AU - Lu, Peng
AU - Lopez, Carla
AU - Steinway, Steve
AU - Scheese, Daniel
AU - Raouf, Zachariah
AU - Tsuboi, Koichi
AU - Ding, Jeffrey
AU - Caputo, Connor
AU - McFarland, Madison
AU - Fulton, William B.
AU - Wang, Sanxia
AU - Wang, Meghan
AU - Prindle, Thomas
AU - Gazit, Vered
AU - Rubin, Deborah C.
AU - Alaish, Samuel
AU - Sodhi, Chhinder
AU - Hackam, David
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-024-52216-6
DO - 10.1038/s41467-024-52216-6
M3 - Article
C2 - 39375337
AN - SCOPUS:85205810048
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 8613
ER -