Tissue Responses to Shiga Toxin in Human Intestinal Organoids

Area of Science:

• Gastroenterology
• Microbiology
• Stem Cell Biology

Background:

• Shiga toxin (Stx)-producing Escherichia coli (e.g., O157:H7) causes bloody diarrhea and potentially life-threatening hemolytic uremic syndrome.
• Murine models and simple cell cultures inadequately represent human intestinal responses to Stx.
• Human stem cell-derived intestinal tissues offer a more complex and relevant model for studying Stx toxicity.

Purpose of the Study:

• To investigate the in vitro and in vivo toxicity of Shiga toxin (Stx) using human intestinal organoid models.
• To examine the complex cellular and tissue-level responses to Stx-induced protein synthesis inhibition.
• To assess the utility of human intestinal organoids (HIOs) and enteroids in modeling Stx effects.

Main Methods:

• Human intestinal organoids (HIOs) and enteroids were exposed to Stx in vitro.
• HIOs, with or without an enteric nervous system, were transplanted into mice for in vivo assessment.
• Cellular responses, including death, proliferation, wound repair, and barrier function, were analyzed.

Main Results:

• Stx induced both necrosis and apoptotic cell death in epithelial and mesenchymal cells.
• Epithelial barrier function was maintained despite cell death, with observed apical to basolateral Stx translocation.
• Mesenchymal cell damage contributed to epithelial damage, and Stx induced mesenchymal-epithelial transition.
• In vivo responses in HIO transplants mirrored in vitro findings.

Conclusions:

• Intestinal tissue responses to Stx-induced protein synthesis inhibition are intricate.
• Human organoid models provide a powerful platform for studying the complex effects of deadly toxins like Stx on human intestinal tissues.
• These models facilitate unprecedented examination of human tissue responses to intestinal injury.