Intelectin-1 binds and alters the localization of the mucus barrier–modifying bacterium Akkermansia muciniphila
Year: 2022
Type: article
Abstract: Intelectin-1 (ITLN1) is a lectin secreted by intestinal epithelial cells (IECs) and upregulated in human ulcerative colitis (UC). We investigated how ITLN1 production is regulated in IECs and the biological effects of ITLN1 at the host-microbiota interface using mouse models. Our data show that ITLN1 upregulation in IECs from UC patients is a consequence of activating the unfolded protein response. Analysis of microbes coated by ITLN1 in vivo revealed a restricted subset of microorganisms, including the mucolytic bacterium Akkermansia muciniphila. Mice overexpressing intestinal ITLN1 exhibited decreased inner colonic mucus layer thickness and closer apposition of A. muciniphila to the epithelial cell surface, similar to alterations reported in UC. The changes in the inner mucus layer were microbiota and A. muciniphila dependent and associated with enhanced sensitivity to chemically induced and T cell-mediated colitis. We conclude that by determining the localization of a select group of bacteria to the mucus layer, ITLN1 modifies this critical barrier. Together, these findings may explain the impact of ITLN1 dysregulation on UC pathogenesis.
DOI: 10.1084/jem.20211938
Authors: Juan D. Matute, Jinzhi Duan, Magdalena B. Flak, Paul Griebel, Jose A. Tascon-Arcila, Shauni Doms, Thomas Hanley, Agne Antanaviciute, Jennifer Gundrum, Jessica L. Mark Welch, Brandon Sit, Shabnam Abtahi, Gwenny M. Fuhler, Joep Grootjans, Florian Tran, Stephanie T. Stengel, James R. White, Niklas Krupka, Dirk Haller, Simon Clare, Trevor D. Lawley, Arthur Kaser, Alison Simmons, Jonathan N. Glickman, Lynn Bry, Philip Rosenstiel, Gary Borisy, Matthew K. Waldor, John F. Baines, Jerrold R. Turner, Richard S. Blumberg
Institutions: Brigham and Women's Hospital, Harvard University, Massachusetts General Hospital, Christian-Albrechts-Universität zu Kiel, University Hospital Schleswig-Holstein, Max Planck Institute for Evolutionary Biology, John Radcliffe Hospital, University of Oxford, MRC Weatherall Institute of Molecular Medicine, MRC Human Immunology Unit, Medical Research Council, The Forsyth Institute, Marine Biological Laboratory, Howard Hughes Medical Institute, Erasmus MC, Amsterdam University Medical Centers, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Resphera Biosciences, Technical University of Munich, Wellcome Sanger Institute, University of Cambridge, Beth Israel Deaconess Medical Center
Language: English
Topic: Inflammatory Bowel Disease
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Funders: Wellcome Trust, Crohn's and Colitis Foundation, National Institute for Health and Care Research, Deutsche Forschungsgemeinschaft, National Institutes of Health, Horizon 2020 Framework Programme, Harvard Digestive Diseases Center, Harvard University, Medical Research Council, European Research Council, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Dental and Craniofacial Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Pediatric Scientist Development Program
Awards: G106007106, G1597886057, G165400314, G1668884940, G1898711858, The function of NOD2 in health and in Crohn's disease., G2624692838, Re-define Crohn’s at a molecular level to identify new biomarkers and therapies, G3436406169, G4004369862, Intestinal Immune Regulation by IgG and FcRn, Can gene-environment interaction in Paneth cells trigger Crohn's disease?., G4792323849, G5649142708, G6325015508, G6472030153, G7314894340, Defining Determinants of Intestinal Barrier Health and Disease, G7352075053, NIHR Senior Investigator Award, Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers., G7869091689, G8289955711, G9000009745, G9000059191, G9000153049, G9000164282, G9000252305, G9000350536, Therapeutic targeting of protein interactions to reverse MLCK1-mediated intestinal barrier loss and ameliorate disease., Regulation of Mucosal Lymphocytes, Intestinal Intelectin-1 regulation of obesity development, Integrated Epithelial and Muscosal Biology, Characterization of Mucosal Lymphocytes, Host-pathogen interactions in experimental cholera, Endoplasmic reticulum stress and intestinal inflammation
OpenAlex ID: W4309660169