Xenotransplanted human organoids identify transepithelial zinc transport as a key mediator of intestinal adaptation
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.
Authors
- Deborah C. Rubin (ORCID: https://orcid.org/0000-0002-4192-909X)
- Sanxia Wang
- Carla M. Lopez (ORCID: https://orcid.org/0000-0003-2521-4315)
- Daniel Scheese
- Johannes W. Duess
- Chhinder P. Sodhi (ORCID: https://orcid.org/0000-0002-1366-4813)
- Zachariah Raouf
- Koichi Tsuboi
- Meghan Wang
- William Fulton (ORCID: https://orcid.org/0000-0001-6685-8753)
- Maame Efua Sampah (ORCID: https://orcid.org/0000-0002-3065-2275)
- Steve Steinway
- Samuel M. Alaish (ORCID: https://orcid.org/0000-0002-8021-3609)
- M.J. McFarland
- Vered Gazit
- Jeffrey Ding (ORCID: https://orcid.org/0000-0003-0461-4045)
- David Joel Hackam (ORCID: https://orcid.org/0000-0001-5195-8807)
- Thomas Prindle
- Hannah Moore
- Peng Lu (ORCID: https://orcid.org/0000-0001-5723-8106)
- Raheel Ahmad (ORCID: https://orcid.org/0000-0002-7189-2056)
- Connor Caputo
Institutions
- Johns Hopkins University (US)
- Washington University in St. Louis (US)
- Johns Hopkins Medicine (US)
- Johns Hopkins Children's Center (US)
- Johns Hopkins Hospital (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-07
- DOI
- https://doi.org/10.1038/s41467-024-52216-6
- Citations
- 2
- Primary Topic
- Trace Elements in Health
- Type
- article
- Field-Weighted Citation Impact
- 0.62
Funders
- Johns Hopkins University
- National Institutes of Health
- National Institute of General Medical Sciences