Journal
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Volume 10, Issue 1, Pages 171-190Publisher
ELSEVIER INC
DOI: 10.1016/j.jcmgh.2020.02.006
Keywords
Intestinal Tissues; Epithelium; Mesenchyme
Categories
Funding
- National Institutes of Health [R0-AI064893, U19-AI116491, R21AI115003, R01AI139027]
- Center for Clinical and Translational Science and Training, Advancing Translational Sciences Award [1UL1TR001425-01]
- National Institute of Diabetes and Digestive and Kidney Diseases of the Digestive Disease Research Core Center in Cincinnati [P30 DK078392]
- National Institute of Diabetes and Digestive and Kidney Diseases
- Farmer Family Foundation
- American Diabetes Association Postdoctoral Fellowship [1-17-PDF-102]
- National Institute of Allergy and Infectious Diseases [U01DK103117]
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BACKGROUND & AIMS: Shiga toxin (Stx)-producing Escherichia coli (eg, O157:H7) infection produces bloody diarrhea, while Stx inhibits protein synthesis and causes the life-threatening systemic complication of hemolytic uremic syndrome. The murine intestinal tract is resistant to O157:H7 and Stx, and human cells in culture fail to model the complex tissue responses to intestinal injury. We used genetically identical, human stem cell-derived intestinal tissues of varying complexity to study Stx toxicity in vitro and in vivo. METHODS: In vitro susceptibility to apical or basolateral exposure to Stx was assessed using human intestinal organoids (HIOs) derived from embryonic stem cells, or enteroids derived from multipotent intestinal stem cells. HIOs contain a lumen, with a single layer of differentiated epithelium surrounded by mesenchymal cells. Enteroids only contain epithelium. In vivo susceptibility was assessed using HIOs, with or without an enteric nervous system, transplanted into mice. RESULTS: Stx induced necrosis and apoptotic death in both epithelial and mesenchymal cells. Responses that require protein synthesis (cellular proliferation and wound repair) also were observed. Epithelial barrier function was maintained even after epithelial cell death was seen, and apical to basolateral translocation of Stx was seen. Tissue cross-talk, in which mesenchymal cell damage caused epithelial cell damage, was observed. Stx induced mesenchymal expression of the epithelial marker E-cadherin, the initial step in mesenchymal-epithelial transition. In vivo responses of HIO transplants injected with Stx mirrored those seen in vitro. CONCLUSIONS: Intestinal tissue responses to protein synthesis inhibition by Stx are complex. Organoid models allow for an unprecedented examination of human tissue responses to a deadly toxin.
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