Naheed Choudhry1, Flora Scott2, Meghan Edgar3, Gareth J Sanger2,3, Paul Kelly2. 1. Barts and The London School of Medicine, Queen Mary, University of London, London, E1 2AT, UK. n.choudhry@qmul.ac.uk. 2. Barts and The London School of Medicine, Queen Mary, University of London, London, E1 2AT, UK. 3. Gastroenterology Drug Discovery Unit, Takeda California, Inc., 10410 Science Center Drive, San Diego, CA, 92121, USA.
Abstract
BACKGROUND: Environmental enteropathy (EE) is associated with stunting, impairment of responses to oral vaccines, and other adverse health consequences in young children throughout the developing world. EE is characterized by chronic low-grade intestinal inflammation and disrupted epithelial barrier integrity, partly resulting from dysregulation of tight junction proteins, observed in other enteropathies such as celiac disease. During EE, this dysregulation of tight junction expression amplifies translocation of pathogenic bacteria across the intestinal mucosa. AIMS: The aim was to determine whether enteropathogen-mediated epithelial barrier failure can be ameliorated using contra-pathogenicity therapies. METHODS: Intestinal epithelial barrier damage was assessed in Caco-2 cells incubated with three important enteropathogens identified in EE patients: Enteropathogenic Escherichia coli (EPEC), Citrobacter rodentium (C. rodentium), and Cryptosporidium parvum (C. parvum). Potential therapeutic molecules were tested to detect effects on transepithelial resistance (TER), bacterial translocation (BT), claudin-4 expression, and regulation of the inflammatory cytokine response. RESULTS: All three enteropathogens compared to uninfected cells, reduced TER (EPEC; p < 0.0001, C. rodentium; p < 0.0001, C. parvum; p < 0.0007), reduced claudin-4 expression, and permitted BT (EPEC; p < 0.0001, C. rodentium; p < 0.0001, C. parvum; p < 0.0003) through the monolayer. Zinc, colostrum, epidermal growth factor, trefoil factor 3, resistin-like molecule-β, hydrocortisone, and the myosin light chain kinase inhibitor ML7 (Hexahydro-1-[(5-iodo-1-naphthalenyl)sulfonyl]-1H-1,4-diazepine hydrochloride); ML7) improved TER (up to 70%) and decreased BT (as much as 96%). Only zinc demonstrated modest antimicrobial activity. CONCLUSION: The enteropathogens impaired intestinal-epithelial barrier integrity with dysregulation of claudin-4 and increased bacterial translocation. Enteropathogen-mediated damage was reduced using contra-pathogenicity agents which mitigated the effects of pathogens without direct antimicrobial activity.
BACKGROUND: Environmental enteropathy (EE) is associated with stunting, impairment of responses to oral vaccines, and other adverse health consequences in young children throughout the developing world. EE is characterized by chronic low-grade intestinal inflammation and disrupted epithelial barrier integrity, partly resulting from dysregulation of tight junction proteins, observed in other enteropathies such as celiac disease. During EE, this dysregulation of tight junction expression amplifies translocation of pathogenic bacteria across the intestinal mucosa. AIMS: The aim was to determine whether enteropathogen-mediated epithelial barrier failure can be ameliorated using contra-pathogenicity therapies. METHODS: Intestinal epithelial barrier damage was assessed in Caco-2 cells incubated with three important enteropathogens identified in EE patients: Enteropathogenic Escherichia coli (EPEC), Citrobacter rodentium (C. rodentium), and Cryptosporidium parvum (C. parvum). Potential therapeutic molecules were tested to detect effects on transepithelial resistance (TER), bacterial translocation (BT), claudin-4 expression, and regulation of the inflammatory cytokine response. RESULTS: All three enteropathogens compared to uninfected cells, reduced TER (EPEC; p < 0.0001, C. rodentium; p < 0.0001, C. parvum; p < 0.0007), reduced claudin-4 expression, and permitted BT (EPEC; p < 0.0001, C. rodentium; p < 0.0001, C. parvum; p < 0.0003) through the monolayer. Zinc, colostrum, epidermal growth factor, trefoil factor 3, resistin-like molecule-β, hydrocortisone, and the myosin light chain kinase inhibitor ML7 (Hexahydro-1-[(5-iodo-1-naphthalenyl)sulfonyl]-1H-1,4-diazepine hydrochloride); ML7) improved TER (up to 70%) and decreased BT (as much as 96%). Only zinc demonstrated modest antimicrobial activity. CONCLUSION: The enteropathogens impaired intestinal-epithelial barrier integrity with dysregulation of claudin-4 and increased bacterial translocation. Enteropathogen-mediated damage was reduced using contra-pathogenicity agents which mitigated the effects of pathogens without direct antimicrobial activity.
Authors: Eduardo Salazar-Lindo; Stephen Allen; David R Brewster; Elizabeth J Elliott; Alessio Fasano; Alan D Phillips; Ian R Sanderson; Phillip I Tarr Journal: J Pediatr Gastroenterol Nutr Date: 2004-06 Impact factor: 2.839
Authors: Micah J Manary; Steven A Abrams; Ian J Griffin; Megan M Quimper; Robert J Shulman; Maria G Hamzo; Zhensheng Chen; Kenneth Maleta; Mark J Manary Journal: Pediatr Res Date: 2010-06 Impact factor: 3.756
Authors: James A Platts-Mills; Sudhir Babji; Ladaporn Bodhidatta; Jean Gratz; Rashidul Haque; Alexandre Havt; Benjamin Jj McCormick; Monica McGrath; Maribel Paredes Olortegui; Amidou Samie; Sadia Shakoor; Dinesh Mondal; Ila Fn Lima; Dinesh Hariraju; Bishnu B Rayamajhi; Shahida Qureshi; Furqan Kabir; Pablo P Yori; Brenda Mufamadi; Caroline Amour; J Daniel Carreon; Stephanie A Richard; Dennis Lang; Pascal Bessong; Esto Mduma; Tahmeed Ahmed; Aldo Aam Lima; Carl J Mason; Anita Km Zaidi; Zulfiqar A Bhutta; Margaret Kosek; Richard L Guerrant; Michael Gottlieb; Mark Miller; Gagandeep Kang; Eric R Houpt Journal: Lancet Glob Health Date: 2015-07-19 Impact factor: 26.763
Authors: Caitlin Naylor; Miao Lu; Rashidul Haque; Dinesh Mondal; Erica Buonomo; Uma Nayak; Josyf C Mychaleckyj; Beth Kirkpatrick; Ross Colgate; Marya Carmolli; Dorothy Dickson; Fiona van der Klis; William Weldon; M Steven Oberste; Jennie Z Ma; William A Petri Journal: EBioMedicine Date: 2015-09-25 Impact factor: 8.143
Authors: Gwenyth O Lee; Benjamin J J McCormick; Jessica C Seidman; Margaret N Kosek; Rashidul Haque; Maribel Paredes Olortegui; Aldo A M Lima; Zulfiqar A Bhutta; Gagandeep Kang; Amidou Samie; Caroline Amour; Carl J Mason; Tahmeed Ahmed; Pablo Peñataro Yori; Domingos B Oliveira; Didar Alam; Sudhir Babji; Pascal Bessong; Estomih Mduma; Sanjaya K Shrestha; Ramya Ambikapathi; Dennis R Lang; Michael Gottlieb; Richard L Guerrant; Laura E Caulfield Journal: Am J Trop Med Hyg Date: 2017-07 Impact factor: 2.345
Authors: Katherine M DiGuilio; Elizabeth Rybakovsky; Reza Abdavies; Romy Chamoun; Colleen A Flounders; Ariel Shepley-McTaggart; Ronald N Harty; James M Mullin Journal: Int J Mol Sci Date: 2022-03-10 Impact factor: 5.923