2. Academic Validation
  3. Mucus sialylation determines intestinal host-commensal homeostasis

Mucus sialylation determines intestinal host-commensal homeostasis

  • Cell. 2022 Mar 31;185(7):1172-1188.e28. doi: 10.1016/j.cell.2022.02.013.
Yikun Yao 1,  Girak Kim 2,  Samantha Shafer 1,  Zuojia Chen 2,  Satoshi Kubo 1,  Yanlong Ji 3,  Jialie Luo 2,  Weiming Yang 4,  Sebastian P Perner 5,  Chrysi Kanellopoulou 1,  Ann Y Park 1,  Ping Jiang 1,  Jian Li 2,  Safa Baris 6,  Elif Karakoc Aydiner 6,  Deniz Ertem 7,  Daniel J Mulder 8,  Neil Warner 9,  Anne M Griffiths 9,  Chani Topf-Olivestone 10,  Michal Kori 10,  Lael Werner 11,  Jodie Ouahed 12,  Michael Field 12,  Chengyu Liu 13,  Benjamin Schwarz 14,  Catharine M Bosio 14,  Sundar Ganesan 15,  Jian Song 16,  Henning Urlaub 17,  Thomas Oellerich 18,  Stacy A Malaker 19,  Lixin Zheng 1,  Carolyn R Bertozzi 20,  Yu Zhang 21,  Helen Matthews 21,  Will Montgomery 22,  Han-Yu Shih 22,  Jiansheng Jiang 23,  Marcus Jones 24,  Aris Baras 24,  Alan Shuldiner 24,  Claudia Gonzaga-Jauregui 25,  Scott B Snapper 12,  Aleixo M Muise 26,  Dror S Shouval 11,  Ahmet Ozen 27,  Kuan-Ting Pan 5,  Chuan Wu 28,  Michael J Lenardo 29
Affiliations

Affiliations

  • 1 Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, NIAID, National Institutes of Health, Bethesda, MD 20892, USA.
  • 2 Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
  • 3 Hematology/Oncology, Department of Medicine II, Johann Wolfgang Goethe University, 60590 Frankfurt am Main, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany; Bioanalytical Mass Spectrometry Group, Max Planck Institute for Multidisciplinary Sciences, 37077 Göttingen, Germany.
  • 4 Section on Biological Chemistry, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, MD 20892, USA.
  • 5 Hematology/Oncology, Department of Medicine II, Johann Wolfgang Goethe University, 60590 Frankfurt am Main, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany.
  • 6 Division of Allergy and Immunology, Department of Pediatrics, School of Medicine, Marmara University, 34722 Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Marmara University, 34722 Istanbul, Turkey.
  • 7 Marmara University School of Medicine, Division of Pediatric Gastroenterology Hepatology and Nutrition, 34854 Istanbul, Turkey.
  • 8 Departments of Pediatrics, Medicine, and Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
  • 9 SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • 10 Pediatric Gastroenterology, Kaplan Medical Center, Pasternak St., POB 1, Rehovot 76100, Israel.
  • 11 Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel.
  • 12 Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA.
  • 13 Transgenic Core Facility, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
  • 14 Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
  • 15 Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • 16 Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD 20892, USA.
  • 17 Bioanalytical Mass Spectrometry Group, Max Planck Institute for Multidisciplinary Sciences, 37077 Göttingen, Germany; Institute of Clinical Chemistry, University Medical Center Göttingen, 37075 Göttingen, Germany.
  • 18 Hematology/Oncology, Department of Medicine II, Johann Wolfgang Goethe University, 60590 Frankfurt am Main, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany; German Cancer Consortium/German Cancer Research Center, 69120 Heidelberg, Germany.
  • 19 Yale University, Department of Chemistry, New Haven, CT 06511, USA.
  • 20 Department of Chemistry, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford, CA 94305, USA.
  • 21 Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA.
  • 22 Neuro-Immune Regulome Unit, National Eye Institute, NIH, Bethesda, MD 20892, USA.
  • 23 Molecular Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA.
  • 24 Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
  • 25 Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA; International Laboratory for Human Genome Research, Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Juriquilla, Querétaro 04510, Mexico.
  • 26 SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, IMS, and Biochemistry, University of Toronto, Toronto, ON M5G 1X8, Canada.
  • 27 The Isil Berat Barlan Center for Translational Medicine, Marmara University, 34722 Istanbul, Turkey; Marmara University School of Medicine, Division of Pediatric Gastroenterology Hepatology and Nutrition, 34854 Istanbul, Turkey.
  • 28 Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].
  • 29 Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, NIAID, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: [email protected].
PMID: 35303419 DOI: 10.1016/j.cell.2022.02.013
Abstract

Intestinal mucus forms the first line of defense against Bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive Bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated Mucin or a Foxo3 inhibitor can ameliorate IBD.

Keywords

ST6GalNAc1; dysbiosis; glycobiology; human genetic disease; inflammatory bowel disease; intestinal homeostasis; intestinal stem cells; mucus barrier; short-chain fatty acids; sialylation.

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