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-Olivestone; Michal 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

doi:10.1016/j.cell.2022.02.013

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 journal › Article › peer-review

117 Scopus citations

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 language	English
Pages (from-to)	1172-1188.e28
Journal	Cell
Volume	185
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2022.02.013
State	Published - 31 Mar 2022
Externally published	Yes

Keywords

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

Access to Document

10.1016/j.cell.2022.02.013

Cite this

Yao, Y., Kim, G., Shafer, S., Chen, Z., Kubo, S., Ji, Y., Luo, J., Yang, W., Perner, S. P., Kanellopoulou, C., Park, A. Y., Jiang, P., Li, J., Baris, S., Aydiner, E. K., Ertem, D., Mulder, D. J., Warner, N., Griffiths, A. M., ... Lenardo, M. J. (2022). Mucus sialylation determines intestinal host-commensal homeostasis. Cell, 185(7), 1172-1188.e28. https://doi.org/10.1016/j.cell.2022.02.013

@article{469b18e846744d93869402f90107cdcd,

title = "Mucus sialylation determines intestinal host-commensal homeostasis",

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",

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

note = "Publisher Copyright: {\textcopyright} 2022",

year = "2022",

month = mar,

day = "31",

doi = "10.1016/j.cell.2022.02.013",

language = "אנגלית",

volume = "185",

pages = "1172--1188.e28",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier",

number = "7",

}

Yao, Y, Kim, G, Shafer, S, Chen, Z, Kubo, S, Ji, Y, Luo, J, Yang, W, Perner, SP, Kanellopoulou, C, Park, AY, Jiang, P, Li, J, Baris, S, Aydiner, EK, Ertem, D, Mulder, DJ, Warner, N, Griffiths, AM, Topf-Olivestone, C, Kori, M, Werner, L, Ouahed, J, Field, M, Liu, C, Schwarz, B, Bosio, CM, Ganesan, S, Song, J, Urlaub, H, Oellerich, T, Malaker, SA, Zheng, L, Bertozzi, CR, Zhang, Y, Matthews, H, Montgomery, W, Shih, HY, Jiang, J, Jones, M, Baras, A, Shuldiner, A, Gonzaga-Jauregui, C, Snapper, SB, Muise, AM, Shouval, DS, Ozen, A, Pan, KT, Wu, C & Lenardo, MJ 2022, 'Mucus sialylation determines intestinal host-commensal homeostasis', Cell, vol. 185, no. 7, pp. 1172-1188.e28. https://doi.org/10.1016/j.cell.2022.02.013

TY - JOUR

T1 - Mucus sialylation determines intestinal host-commensal homeostasis

AU - Yao, Yikun

AU - Kim, Girak

AU - Shafer, Samantha

AU - Chen, Zuojia

AU - Kubo, Satoshi

AU - Ji, Yanlong

AU - Luo, Jialie

AU - Yang, Weiming

AU - Perner, Sebastian P.

AU - Kanellopoulou, Chrysi

AU - Park, Ann Y.

AU - Jiang, Ping

AU - Li, Jian

AU - Baris, Safa

AU - Aydiner, Elif Karakoc

AU - Ertem, Deniz

AU - Mulder, Daniel J.

AU - Warner, Neil

AU - Griffiths, Anne M.

AU - Topf-Olivestone, Chani

AU - Kori, Michal

AU - Werner, Lael

AU - Ouahed, Jodie

AU - Field, Michael

AU - Liu, Chengyu

AU - Schwarz, Benjamin

AU - Bosio, Catharine M.

AU - Ganesan, Sundar

AU - Song, Jian

AU - Urlaub, Henning

AU - Oellerich, Thomas

AU - Malaker, Stacy A.

AU - Zheng, Lixin

AU - Bertozzi, Carolyn R.

AU - Zhang, Yu

AU - Matthews, Helen

AU - Montgomery, Will

AU - Shih, Han Yu

AU - Jiang, Jiansheng

AU - Jones, Marcus

AU - Baras, Aris

AU - Shuldiner, Alan

AU - Gonzaga-Jauregui, Claudia

AU - Snapper, Scott B.

AU - Muise, Aleixo M.

AU - Shouval, Dror S.

AU - Ozen, Ahmet

AU - Pan, Kuan Ting

AU - Wu, Chuan

AU - Lenardo, Michael J.

PY - 2022/3/31

Y1 - 2022/3/31

N2 - 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.

AB - 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.

KW - ST6GalNAc1

KW - dysbiosis

KW - glycobiology

KW - human genetic disease

KW - inflammatory bowel disease

KW - intestinal homeostasis

KW - intestinal stem cells

KW - mucus barrier

KW - short-chain fatty acids

KW - sialylation

UR - http://www.scopus.com/inward/record.url?scp=85127035413&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2022.02.013

DO - 10.1016/j.cell.2022.02.013

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 35303419

AN - SCOPUS:85127035413

SN - 0092-8674

VL - 185

SP - 1172-1188.e28

JO - Cell

JF - Cell

IS - 7

ER -

Mucus sialylation determines intestinal host-commensal homeostasis

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this