Mucus sialylation determines intestinal host-commensal homeostasis

Yikun Yao, Girak Kim, Samantha Shafer, Zuojia Chen, Satoshi Kubo, Yanlong Ji, Jialie Luo, Weiming Yang, Sebastian P. Perner, Chrysi Kanellopoulou, Ann Y. Park, Ping Jiang, Jian Li, Safa Baris, Elif Karakoc Aydiner, Deniz Ertem, Daniel J. Mulder, Neil Warner, Anne M. Griffiths, Chani Topf-OlivestoneMichal Kori, Lael Werner, Jodie Ouahed, Michael Field, Chengyu Liu, Benjamin Schwarz, Catharine M. Bosio, Sundar Ganesan, Jian Song, Henning Urlaub, Thomas Oellerich, Stacy A. Malaker, Lixin Zheng, Carolyn R. Bertozzi, Yu Zhang, Helen Matthews, Will Montgomery, Han Yu Shih, Jiansheng Jiang, Marcus Jones, Aris Baras, Alan Shuldiner, Claudia Gonzaga-Jauregui, Scott B. Snapper, Aleixo M. Muise, Dror S. Shouval, Ahmet Ozen, Kuan Ting Pan, Chuan Wu*, Michael J. Lenardo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1172-1188.e28
JournalCell
Volume185
Issue number7
DOIs
StatePublished - 31 Mar 2022
Externally publishedYes

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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