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Organoid model unveils response to Shiga toxin

Key clinical point: Exposure to Shiga toxin induces a complex intestinal response involving transcription, necrosis, apoptotic cell death, cellular proliferation, and cross-talk between epithelial and mesenchymal cells.

Major finding: Human intestinal organoids expressed glycolipid Gb3, the Shiga toxin receptor, and the study described how the toxin can quickly access the circulatory system.

Study details: A translational study evaluating responses to Shiga toxin in human intestinal organoids, both in culture and transplanted into mice.

Disclosures: The study was funded by the National Institutes of Health, the Center for Clinical and Translational Science, the National Institute of Diabetes and Digestive and Kidney Diseases, and others. The investigators disclosed no conflicts of interest.

Citation:

Pradhan S et al. Cell Mol Gastroenterol Hepatol. 2020 Mar 5. doi: 10.1016/j.jcmgh.2020.02.006.

Commentary:

Limited therapies exist to mitigate the life-threatening sequelae of Shiga toxin (Stx)–producing Escherichia coli (STEC) infections. Stx continues to be a leading cause of hemolytic uremic syndrome and can devastate the kidneys, central nervous system, and other vital organs. Conflicting results from animal models and cell lines have left important questions unanswered, slowing therapy development. This study by Pradhan et al. takes advantage of the human intestinal organoid system to provide insight to questions pertinent to understanding Stx mechanism of action. Importantly, the authors find that intestinal epithelial cells (IECs) are a direct target of Stx and express the Stx receptor, Gb3, a point that had not been previously well established. They further confirm that IECs efficiently transport Stx from the apical to basolateral surface, before barrier integrity is compromised. This likely allows Stx to rapidly access circulation and other affected organs to cause disease.

Perhaps the most promising aspects of this study and model system center on the demonstrated ability to study Stx in in vitro cultures that encompass much of the complex developmental transitions and cell-cell interactions pertinent to disease. Thus, while the clinical relevance of in vivo modeling with transplanted human intestinal organoids needs further clarification, critical questions can now be explored such as: During STEC infection, which are the important mucosal cell-cell interactions? Do immature IECs express the Stx receptor and respond differently than mature IECs? And how do we block Stx movement across IECs and prevent its access to circulation? These questions can all be addressed.

Nicole Maloney Belle, MD, PhD, is an instructor of medicine, division of gastroenterology and hepatology, at the University of Pennsylvania, Philadelphia. She has no conflicts.