PMID- 36371425 OWN - NLM STAT- MEDLINE DCOM- 20221115 LR - 20231202 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 13 IP - 1 DP - 2022 Nov 12 TI - Enterotoxigenic Escherichia coli heat-labile toxin drives enteropathic changes in small intestinal epithelia. PG - 6886 LID - 10.1038/s41467-022-34687-7 [doi] LID - 6886 AB - 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. CI - (c) 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. FAU - Sheikh, Alaullah AU - Sheikh A AUID- ORCID: 0000-0002-2972-6978 AD - Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. FAU - Tumala, Brunda AU - Tumala B AD - Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. FAU - Vickers, Tim J AU - Vickers TJ AD - Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. FAU - Martin, John C AU - Martin JC AD - The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, 63110, USA. FAU - Rosa, Bruce A AU - Rosa BA AUID- ORCID: 0000-0002-6820-446X AD - Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. AD - The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, 63110, USA. FAU - Sabui, Subrata AU - Sabui S AD - Departments of Medicine and Physiology/Biophysics, School of Medicine, University of California-Irvine, Irvine, CA, 92697, USA. AD - Department of Research, VA Medical Center, Long Beach, CA, 90822, USA. FAU - Basu, Supratim AU - Basu S AUID- ORCID: 0000-0002-7904-3569 AD - Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. FAU - Simoes, Rita D AU - Simoes RD AD - Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. FAU - Mitreva, Makedonka AU - Mitreva M AUID- ORCID: 0000-0001-9572-3436 AD - Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. AD - The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, 63110, USA. FAU - Storer, Chad AU - Storer C AD - The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, 63110, USA. AD - Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110, USA. FAU - Tyksen, Erik AU - Tyksen E AUID- ORCID: 0000-0001-6362-0141 AD - The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, 63110, USA. AD - Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110, USA. FAU - Head, Richard D AU - Head RD AD - The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, 63110, USA. AD - Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110, USA. FAU - Beatty, Wandy AU - Beatty W AD - Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO, 63110, USA. FAU - Said, Hamid M AU - Said HM AD - Departments of Medicine and Physiology/Biophysics, School of Medicine, University of California-Irvine, Irvine, CA, 92697, USA. AD - Department of Research, VA Medical Center, Long Beach, CA, 90822, USA. FAU - Fleckenstein, James M AU - Fleckenstein JM AUID- ORCID: 0000-0002-1148-697X AD - Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. jfleckenstein@wustl.edu. AD - Infectious Diseases, Medicine Service, Veterans Affairs Saint Louis Health Care System, Saint Louis, MO, 63106, USA. jfleckenstein@wustl.edu. LA - eng GR - R01 AI089894/AI/NIAID NIH HHS/United States GR - R01 AI126887/AI/NIAID NIH HHS/United States GR - I01 BX004825/BX/BLRD VA/United States GR - P30 DK052574/DK/NIDDK NIH HHS/United States GR - UL1 TR002345/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20221112 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - D9K3SN2LNY (heat-labile enterotoxin, E coli) RN - 0 (Enterotoxins) RN - 0 (Escherichia coli Proteins) SB - IM MH - Mice MH - Animals MH - Enterotoxins/genetics MH - *Escherichia coli Proteins/genetics/metabolism MH - *Enterotoxigenic Escherichia coli/genetics/metabolism MH - *Escherichia coli Infections/prevention & control MH - Diarrhea MH - *Malnutrition PMC - PMC9653437 COIS- R.D.H. and C.S. may receive royalty income based on the CompBio technology developed by R.D.H. and licensed by Washington University to PercayAI. The remaining authors declare no competing interests. EDAT- 2022/11/14 06:00 MHDA- 2022/11/16 06:00 PMCR- 2022/11/12 CRDT- 2022/11/13 00:05 PHST- 2022/06/07 00:00 [received] PHST- 2022/11/01 00:00 [accepted] PHST- 2022/11/14 06:00 [pubmed] PHST- 2022/11/16 06:00 [medline] PHST- 2022/11/13 00:05 [entrez] PHST- 2022/11/12 00:00 [pmc-release] AID - 10.1038/s41467-022-34687-7 [pii] AID - 34687 [pii] AID - 10.1038/s41467-022-34687-7 [doi] PST - epublish SO - Nat Commun. 2022 Nov 12;13(1):6886. doi: 10.1038/s41467-022-34687-7.