Acetate,a metabolic product of Heligmosomoides polygyrus,facilitates intestinal epithelial barrier breakdown in a FFAR2-dependent manner |
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| Affiliation: | 1. Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany;2. Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH-1015, Switzerland;3. Center of Allergy and Environment, Technical University of Munich and Helmholtz Zentrum München, Munich, Germany;4. Centre of Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom;5. Department of Infection Biology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany;6. Department of Immunology, Monash University, Clayton, Victoria, Australia;1. Laboratory of Parasitology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium;2. Kreavet, Hendrik Mertensstraat 17, 9150 Kruibeke, Belgium;3. Royal Meteorological Institute, Avenue Circulaire 3, 1180 Brussels, Belgium;4. Institute for Parasitology, Centre for Infection Medicine, University of Veterinary Medicine Hannover, Bünteweg 9, 30559 Hannover, Germany;1. Mitrani Department of Desert Ecology, Swiss Institute for Dryland Environmental and Energy Research, Jacob Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Sede Boqer Campus, Midreshet Ben-Gurion, Israel;2. French Associates Institute for Agriculture and Biotechnology of Drylands, Jacob Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Sede Boqer Campus, Midreshet Ben-Gurion, Israel;1. Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada;2. Host-Parasite Interactions (HPI) Program, University of Calgary, Calgary, Alberta, Canada;3. Institute of Biodiversity Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Garscube Campus, Glasgow, UK;4. Tree of Life, Wellcome Sanger Institute, Cambridge, UK;5. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK;6. University of Edinburgh, Roslin Institute, Easter Bush Veterinary Centre, Roslin, Midlothian, UK;7. Department of Parasitology FVAS, University of Agriculture, D.I. Khan, Pakistan;8. Molecular Biosciences, Northwestern University, Evanston, IL, USA;9. Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada;1. Department of Environmental and Occupational Health, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, USA;2. Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, USA;3. Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, USA;4. Institute of Parasitic Diseases, Sichuan Center for Disease Control and Prevention, Chengdu, China |
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| Abstract: | Approximately 2 billion people worldwide and a significant part of the domestic livestock are infected with soil-transmitted helminths, of which many establish chronic infections causing substantial economic and welfare burdens. Beside intensive research on helminth-triggered mucosal and systemic immune responses, the local mechanism that enables infective larvae to cross the intestinal epithelial barrier and invade mucosal tissue remains poorly addressed. Here, we show that Heligmosomoides polygyrus infective L3s secrete acetate and that acetate potentially facilitates paracellular epithelial tissue invasion by changed epithelial tight junction claudin expression. In vitro, impedance-based real-time epithelial cell line barrier measurements together with ex vivo functional permeability assays in intestinal organoid cultures revealed that acetate decreased intercellular barrier function via the G-protein coupled free fatty acid receptor 2 (FFAR2, GPR43). In vivo validation experiments in FFAR2?/? mice showed lower H. polygyrus burdens, whereas oral acetate-treated C57BL/6 wild type mice showed higher burdens. These data suggest that locally secreted acetate – as a metabolic product of the energy metabolism of H. polygyrus L3s – provides a significant advantage to the parasite in crossing the intestinal epithelial barrier and invading mucosal tissues. This is the first and a rate-limiting step for helminths to establish chronic infections in their hosts and if modulated could have profound consequences for their life cycle. |
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| Keywords: | Acetate Microbiota Barrier function Intestinal permeability Helminths |
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