Mucus sialylation determines intestinal host-commensal homeostasis

Cell. 2022 Mar 31;185(7):1172-1188.e28. doi: 10.1016/j.cell.2022.02.013. Epub 2022 Mar 17.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Gastrointestinal Microbiome*
  • Homeostasis
  • Humans
  • Inflammatory Bowel Diseases* / genetics
  • Inflammatory Bowel Diseases* / metabolism
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / microbiology
  • Mice
  • Mucus / metabolism
  • Sialyltransferases / genetics*
  • Sialyltransferases / metabolism
  • Symbiosis


  • Sialyltransferases
  • CMP-N-acetylneuraminate-alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase