Enterotoxigenic Escherichia coli heat-labile toxin drives enteropathic changes in small intestinal epithelia

Alaullah Sheikh, Brunda Tumala, Tim J. Vickers, John C. Martin, Bruce A. Rosa, Subrata Sabui, Supratim Basu, Rita D. Simoes, Makedonka Mitreva, Chad Storer, Erik Tyksen, Richard D. Head, Wandy Beatty, Hamid M. Said and James M. Fleckenstein ()
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Alaullah Sheikh: Washington University School of Medicine
Brunda Tumala: Washington University School of Medicine
Tim J. Vickers: Washington University School of Medicine
John C. Martin: Washington University School of Medicine
Bruce A. Rosa: Washington University School of Medicine
Subrata Sabui: University of California-Irvine
Supratim Basu: Washington University School of Medicine
Rita D. Simoes: Washington University School of Medicine
Makedonka Mitreva: Washington University School of Medicine
Chad Storer: Washington University School of Medicine
Erik Tyksen: Washington University School of Medicine
Richard D. Head: Washington University School of Medicine
Wandy Beatty: Washington University School of Medicine
Hamid M. Said: University of California-Irvine
James M. Fleckenstein: Washington University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Enterotoxigenic E. coli (ETEC) produce heat-labile (LT) and/or heat-stable (ST) enterotoxins, and commonly cause diarrhea in resource-poor regions. ETEC have been linked repeatedly to sequelae in children including enteropathy, malnutrition, and growth impairment. Although cellular actions of ETEC enterotoxins leading to diarrhea are well-established, their contributions to sequelae remain unclear. LT increases cellular cAMP to activate protein kinase A (PKA) that phosphorylates ion channels driving intestinal export of salt and water resulting in diarrhea. As PKA also modulates transcription of many genes, we interrogated transcriptional profiles of LT-treated intestinal epithelia. Here we show that LT significantly alters intestinal epithelial gene expression directing biogenesis of the brush border, the major site for nutrient absorption, suppresses transcription factors HNF4 and SMAD4 critical to enterocyte differentiation, and profoundly disrupts microvillus architecture and essential nutrient transport. In addition, ETEC-challenged neonatal mice exhibit substantial brush border derangement that is prevented by maternal vaccination with LT. Finally, mice repeatedly challenged with toxigenic ETEC exhibit impaired growth recapitulating the multiplicative impact of recurring ETEC infections in children. These findings highlight impacts of ETEC enterotoxins beyond acute diarrheal illness and may inform approaches to prevent major sequelae of these common infections including malnutrition that impact millions of children.

Date: 2022
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DOI: 10.1038/s41467-022-34687-7

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