EnterotoxigenicEscherichia coliheat-labile toxin drives enteropathic changes in small intestinal epithelia

Abstract

Enterotoxigenic E. coli (ETEC), produce heat-labile (LT) and/or heat-stable (ST) enterotoxins, and are a common cause of diarrhea in children of resource-poor regions. ETEC have also been linked repeatedly to poorly understood sequelae including enteropathy, malnutrition, and growth impairment. While the cellular actions of ETEC enterotoxins leading to diarrhea are well-established, their potential contribution to subsequent pathology is unclear. LT stimulates cellular cAMP production to activate protein kinase A (PKA) which phosphorylates cellular ion channels that drive export of salt and water into the intestinal lumen resulting in diarrhea. However, as PKA exhibits broad kinase activity and its activated catalytic subunits modulate transcription of many genes, we interrogated the transcriptional profiles of LT-treated small intestinal epithelia. These studies demonstrated toxin-induced changes in hundreds of genes including those required for biogenesis and function of the brush border, the major site absorption of nutrients, and suppression of a key transcription factor, HNF4, critical to differentiation of intestinal epithelia. Accordingly, LT treatment of intestinal epithelial cells significantly disrupted the absorptive microvillus architecture and altered transport of essential nutrients. In addition, challenge of neonatal mice with LT-producing ETEC recapitulated the architectural derangement of the brush border while maternal vaccination with LT prevented brush border disruption in ETEC-challenged neonatal mice. These findings highlight impacts of ETEC enterotoxins beyond acute diarrheal illness and may inform approaches to mitigate and prevent major sequelae including malnutrition that impact millions of young children.

Destruction of the brush border by Salmonella enterica sv. Typhimurium subverts resorption by polarized epithelial cells

“…Nevertheless, pathogenic bacteria such as enteropathogenic Escherichia coli (EPEC), enterohaemorrhagic E. coli (EHEC), enterotoxigenic E. coli (ETEC), Helicobacter pylori, or Salmonella enterica can disturb the integrity and function of the intestinal epithelium. After adhesion to host cells, these pathogens efface MV by translocation of virulence proteins that modify (a) actin, (b) increase the adhesion surface, in the case of EPEC and H. pylori, or (c) alter the transporter expression and localization by ribosylating toxins as the labile toxin (LT) of ETEC (Segal et al, 1996;Tan et al, 2009;Wong et al, 2011;Sheikh et al, 2022;Felipe-Lopez et al, 2023).…”

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“…Nevertheless, pathogenic bacteria such as enteropathogenic Escherichia coli (EPEC), enterohaemorrhagic E. coli (EHEC), enterotoxigenic E. coli (ETEC), Helicobacter pylori, or Salmonella enterica can disturb the integrity and function of the intestinal epithelium. After adhesion to host cells, these pathogens efface MV by translocation of virulence proteins that modify (a) actin, (b) increase the adhesion surface, in the case of EPEC and H. pylori, or (c) alter the transporter expression and localization by ribosylating toxins as the labile toxin (LT) of ETEC (Segal et al, 1996;Tan et al, 2009;Wong et al, 2011;Sheikh et al, 2022;Felipe-Lopez et al, 2023).…”