Enterotoxigenic Escherichia coli heat-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 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.

Validation of a Human Challenge Model Using an LT-Expressing Enterotoxigenic E. coli Strain (LSN03-016011) and Characterization of Potential Amelioration of Disease by an Investigational Oral Vaccine Candidate (VLA1701)

“…Anti-LT reactive antibodies have also been shown to modulate the severity of ETEC-associated illness in a CHIM [31], to protect against ETEC strains producing only LT in field studies, and to reduce the severity of ETEC-associated disease in general in the field [31,32,44]. Similarly, higher anti-CTB serum IgA titers are associated with a reduced risk of ETEC-attributable travelers' diarrhea and lower disease severity scores in U.S. travelers to Guatemala and Mexico [30,31,45]. This study also provides the first information on the systemic and mucosal immunogenicity of VLA1701.…”

Jian-Pi-Yin decoction attenuates lactose-induced chronic diarrhea in rats by regulating GLP-1 and reducing NHE3 ubiquitination and phosphorylation

“…GLP-1 binds to GLP-1R to generate cAMP, which activates PKA by binding to the PKA regulatory subunit, RIS or RIS. On the one hand, the catalytic subunit (C) of PKA is released from the PKA tetramer and phosphorylates NHE3 at Serine 552, reducing plasma membrane NHE3 expression [ 31 ]. On the other hand, it can reduce the expression of USP7 or USP10, increase the ubiquitination level of NHE3, enhance the endocytic transport of NHE3, and reduce the surface membrane abundance of NHE3, both of which can lead to a significant reduction in the total amount of NHE3 protein [ 32 ].…”

Interactions of pathogenic Escherichia coli with CEACAMs

“…The activated CREB transcription factor is then free to engage multiple cAMP-responsive elements (CRE, e.g ., 5’-TGACGTCA-3’) in the regulatory regions of approximately 4000 genes within the human genome. Not surprisingly, recent studies of transcriptional modulation by LT have revealed that it impacts the expression of hundreds of genes in intestinal epithelial cells ( 63 ).…”