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Article ; Online: Goblet cells need some stress

Malin E.V. Johansson / Gunnar C. Hansson

The Journal of Clinical Investigation, Vol 132, Iss

2022 Volume 17

Abstract: The intestinal tract is protected by epithelium-covering mucus, which is constantly renewed by goblet cells, a specialized type of epithelial cell. Mucus is largely composed of MUC2 mucin, an enormous molecule that poses a high demand on the endoplasmic ... ...

Abstract	The intestinal tract is protected by epithelium-covering mucus, which is constantly renewed by goblet cells, a specialized type of epithelial cell. Mucus is largely composed of MUC2 mucin, an enormous molecule that poses a high demand on the endoplasmic reticulum (ER) for proper folding and protein assembly, creating a challenge for the secretory machinery in goblet cells. In this issue of the JCI, Grey et al. reveal that the ER resident protein and folding sensor ERN2 (also known as IRE1β) was instrumental for goblet cells to produce sufficient amounts of mucus to form a protective mucus layer. In the absence of ERN2, mucus production was reduced, impairing the mucus barrier, which allowed bacteria to penetrate and cause an epithelial cell stress response. This study emphasizes the importance of a controlled unfolded protein response (UPR) for goblet cell secretion.
Keywords	Medicine ; R
Language	English
Publishing date	2022-09-01T00:00:00Z
Publisher	American Society for Clinical Investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The role of goblet cells and mucus in intestinal homeostasis.

Gustafsson, Jenny K / Johansson, Malin E V

Nature reviews. Gastroenterology & hepatology

2022 Volume 19, Issue 12, Page(s) 785–803

Abstract: The intestinal tract faces numerous challenges that require several layers of defence. The tight epithelium forms a physical barrier that is further protected by a mucus layer, which provides various site-specific protective functions. Mucus is produced ... ...

Abstract	The intestinal tract faces numerous challenges that require several layers of defence. The tight epithelium forms a physical barrier that is further protected by a mucus layer, which provides various site-specific protective functions. Mucus is produced by goblet cells, and as a result of single-cell RNA sequencing identifying novel goblet cell subpopulations, our understanding of their various contributions to intestinal homeostasis has improved. Goblet cells not only produce mucus but also are intimately linked to the immune system. Mucus and goblet cell development is tightly regulated during early life and synchronized with microbial colonization. Dysregulation of the developing mucus systems and goblet cells has been associated with infectious and inflammatory conditions and predisposition to chronic disease later in life. Dysfunctional mucus and altered goblet cell profiles are associated with inflammatory conditions in which some mucus system impairments precede inflammation, indicating a role in pathogenesis. In this Review, we present an overview of the current understanding of the role of goblet cells and the mucus layer in maintaining intestinal health during steady-state and how alterations to these systems contribute to inflammatory and infectious disease.
MeSH term(s)	Humans ; Goblet Cells/pathology ; Goblet Cells/physiology ; Mucins/genetics ; Mucus ; Intestines ; Homeostasis ; Intestinal Mucosa/pathology
Chemical Substances	Mucins
Language	English
Publishing date	2022-09-12
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2493722-8
ISSN	1759-5053 ; 1759-5045
ISSN (online)	1759-5053
ISSN	1759-5045
DOI	10.1038/s41575-022-00675-x
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Article ; Online: Forming a mucus barrier along the colon.

Birchenough, George M H / Johansson, Malin E V

Science (New York, N.Y.)

2020 Volume 370, Issue 6515, Page(s) 402–403

MeSH term(s)	Colon ; Digestive System ; Microbiota ; Mucus
Language	English
Publishing date	2020-10-22
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abe7194
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Article ; Online: GLP-1R signaling modulates colonic energy metabolism, goblet cell number and survival in the absence of gut microbiota.

Greiner, Thomas U / Koh, Ara / Peris, Eduard / Bergentall, Mattias / Johansson, Malin E V / Hansson, Gunnar C / Drucker, Daniel J / Bäckhed, Fredrik

Molecular metabolism

2024 Volume 83, Page(s) 101924

Abstract: Objectives: Gut microbiota increases energy availability through fermentation of dietary fibers to short-chain fatty acids in conventionally raised mice. Energy deficiency in germ-free (GF) mice increases glucagon-like peptide-1 (GLP-1) levels, which ... ...

Abstract	Objectives: Gut microbiota increases energy availability through fermentation of dietary fibers to short-chain fatty acids in conventionally raised mice. Energy deficiency in germ-free (GF) mice increases glucagon-like peptide-1 (GLP-1) levels, which slows intestinal transit. To further analyze the role of GLP-1-mediated signaling in this model of energy deficiency, we re-derived mice lacking GLP-1 receptor (GLP-1R KO) as GF. Methods: GLP-1R KO mice were rederived as GF through hysterectomy and monitored for 30 weeks. Mice were subjected to rescue experiments either through feeding an energy-rich diet or colonization with a normal cecal microbiota. Histology and intestinal function were assessed at different ages. Intestinal organoids were assessed to investigate stemness. Results: Unexpectedly, 25% of GF GLP-1R KO mice died before 20 weeks of age, associated with enlarged ceca, increased cecal water content, increased colonic expression of apical ion transporters, reduced number of goblet cells and loss of colonic epithelial integrity. Colonocytes from GLP-1R KO mice were energy-deprived and exhibited increased ER-stress; mitochondrial fragmentation, increased oxygen levels and loss of stemness. Restoring colonic energy levels either by feeding a Western-style diet or colonization with a normal gut microbiota normalized gut phenotypes and prevented lethality. Conclusions: Our findings reveal a heretofore unrecognized role for GLP-1R signaling in the maintenance of colonic physiology and survival during energy deprivation.
MeSH term(s)	Animals ; Glucagon-Like Peptide-1 Receptor/metabolism ; Gastrointestinal Microbiome/physiology ; Mice ; Energy Metabolism ; Goblet Cells/metabolism ; Colon/metabolism ; Colon/microbiology ; Mice, Knockout ; Signal Transduction ; Mice, Inbred C57BL ; Male ; Female ; Glucagon-Like Peptide 1/metabolism
Chemical Substances	Glucagon-Like Peptide-1 Receptor ; Glp1r protein, mouse ; Glucagon-Like Peptide 1 (89750-14-1)
Language	English
Publishing date	2024-03-21
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2708735-9
ISSN	2212-8778 ; 2212-8778
ISSN (online)	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2024.101924
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Article ; Online: Childbirth rates in women with myeloproliferative neoplasms.

Landtblom, Anna Ravn / Andersson, Therese M-L / Johansson, Anna L V / Lundberg, Frida E / Samuelsson, Jan / Björkholm, Magnus / Hultcrantz, Malin

Leukemia

2024

Abstract: Myeloproliferative neoplasms (MPN) are associated with inferior pregnancy outcome, however, little is known about fertility and childbearing potential in women with MPN. In this study we aimed to describe reproductive patterns, as well as to quantify ... ...

Abstract	Myeloproliferative neoplasms (MPN) are associated with inferior pregnancy outcome, however, little is known about fertility and childbearing potential in women with MPN. In this study we aimed to describe reproductive patterns, as well as to quantify risk of miscarriage and stillbirth. Women aged 15-44 years with an MPN diagnosis 1973-2018, were identified in Swedish health care registers, and age-matched 1:4 to population controls. We identified 1141 women with MPN and 4564 controls. Women with MPN had a lower rate of childbirth (hazard ratio [HR] with 95% confidence interval was 0.78 (0.68-0.90)). Subgroup analysis showed that the rate was not significantly reduced in essential thrombocythemia, HR 1.02 (0.86-1.22) while the HR was 0.50 (0.33-0.76) in PV and 0.45 (0.28-0.74) in PMF. The risk of miscarriage was not significantly increased before MPN diagnosis, the HR during follow-up after diagnosis was 1.25 (0.89-1.76). Women with MPN were more likely to have had a previous stillbirth. Women with MPN had fewer children at diagnosis, and fewer children in total. In conclusion, the childbirth rate was lower among women with MPN than controls, but not among women with essential thrombocythemia.
Language	English
Publishing date	2024-03-09
Publishing country	England
Document type	Journal Article
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-024-02216-8
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Article ; Online: The intestinal MUC2 mucin C-terminus is stabilized by an extra disulfide bond in comparison to von Willebrand factor and other gel-forming mucins

Pablo Gallego / Maria-Jose Garcia-Bonete / Sergio Trillo-Muyo / Christian V. Recktenwald / Malin E. V. Johansson / Gunnar C. Hansson

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 9

Abstract: The MUC2 mucin is a large, highly glycosylated polymer that builds the intestinal mucus. Here, the authors generate a high-resolution structural model of the 800 amino acid C-terminal dimer including its glycans. Stabilization is achieved by interdimer ... ...

Abstract	The MUC2 mucin is a large, highly glycosylated polymer that builds the intestinal mucus. Here, the authors generate a high-resolution structural model of the 800 amino acid C-terminal dimer including its glycans. Stabilization is achieved by interdimer disulfide-bonds in both ends, essential for a stable mucus barrier.
Keywords	Science ; Q
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: The intestinal MUC2 mucin C-terminus is stabilized by an extra disulfide bond in comparison to von Willebrand factor and other gel-forming mucins.

Gallego, Pablo / Garcia-Bonete, Maria-Jose / Trillo-Muyo, Sergio / Recktenwald, Christian V / Johansson, Malin E V / Hansson, Gunnar C

Nature communications

2023 Volume 14, Issue 1, Page(s) 1969

Abstract: The MUC2 mucin polymer is the main building unit of the intestinal mucus layers separating intestinal microbiota from the host epithelium. The MUC2 mucin is a large glycoprotein with a C-terminal domain similar to the MUC5AC and MUC5B mucins and the von ... ...

Abstract	The MUC2 mucin polymer is the main building unit of the intestinal mucus layers separating intestinal microbiota from the host epithelium. The MUC2 mucin is a large glycoprotein with a C-terminal domain similar to the MUC5AC and MUC5B mucins and the von Willebrand factor (VWF). A structural model of the C-terminal part of MUC2, MUC2-C, was generated by combining Cryo-electron microscopy, AlphaFold prediction, information of its glycosylation, and small angle X-ray scattering information. The globular VWD4 assembly in the N-terminal of MUC2-C is followed by 3.5 linear VWC domains that form an extended flexible structure before the C-terminal cystine-knot. All gel-forming mucins and VWF form tail-tail disulfide-bonded dimers in their C-terminal cystine-knot domain, but interestingly the MUC2 mucin has an extra stabilizing disulfide bond on the N-terminal side of the VWD4 domain, likely essential for a stable intestinal mucus barrier.
MeSH term(s)	von Willebrand Factor ; Cystine ; Cryoelectron Microscopy ; Intestines ; Mucin 5AC
Chemical Substances	von Willebrand Factor ; Cystine (48TCX9A1VT) ; Mucin 5AC
Language	English
Publishing date	2023-04-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-37666-8
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Article ; Online: Clearance of small intestinal crypts involves goblet cell mucus secretion by intracellular granule rupture and enterocyte ion transport.

Dolan, Brendan / Ermund, Anna / Martinez-Abad, Beatriz / Johansson, Malin E V / Hansson, Gunnar C

Science signaling

2022 Volume 15, Issue 752, Page(s) eabl5848

Abstract: Goblet cells in the small intestinal crypts contain large numbers of mucin granules that are rapidly discharged to clean bacteria from the crypt. Because acetylcholine released by neuronal and nonneuronal cells controls many aspects of intestinal ... ...

Abstract	Goblet cells in the small intestinal crypts contain large numbers of mucin granules that are rapidly discharged to clean bacteria from the crypt. Because acetylcholine released by neuronal and nonneuronal cells controls many aspects of intestinal epithelial function, we used tissue explants and organoids to investigate the response of the small intestinal crypt to cholinergic stimulation. The activation of muscarinic acetylcholine receptors initiated a coordinated and rapid emptying of crypt goblet cells that flushed the crypt contents into the intestinal lumen. Cholinergic stimulation induced an expansion of the granule contents followed by intracellular rupture of the mucin granules. The mucus expanded intracellularly before the rupture of the goblet cell apical membrane and continued to expand after its release into the crypt lumen. The goblet cells recovered from membrane rupture and replenished their stores of mucin granules. Mucus secretion from the goblet cells depended on Ca
MeSH term(s)	Acetylcholine/metabolism ; Acetylcholine/pharmacology ; Cholinergic Agents/metabolism ; Enterocytes/metabolism ; Goblet Cells ; Intestinal Mucosa/metabolism ; Ion Transport ; Mucins/metabolism ; Mucus/metabolism ; Water/metabolism
Chemical Substances	Cholinergic Agents ; Mucins ; Water (059QF0KO0R) ; Acetylcholine (N9YNS0M02X)
Language	English
Publishing date	2022-09-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.abl5848
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Article ; Online: Mucus layers in inflammatory bowel disease.

Johansson, Malin E V

Inflammatory bowel diseases

2014 Volume 20, Issue 11, Page(s) 2124–2131

Abstract: The intestinal epithelium is covered with mucus with the main structural building block being the densely O-glycosylated MUC2 mucin. The intestinal epithelium is exposed to ingested material, our digestive machinery, and large amounts of microorganisms. ... ...

Abstract	The intestinal epithelium is covered with mucus with the main structural building block being the densely O-glycosylated MUC2 mucin. The intestinal epithelium is exposed to ingested material, our digestive machinery, and large amounts of microorganisms. Mucus is the first line of defense and aids to limit exposure to all these threats to the epithelium. In the small intestine, mucus acts as a matrix, which contains antimicrobial products, such as defensins and immunoglobulin A that limit epithelial exposure to the luminal bacteria. In the colon, the stratified inner mucus layer acts as a physical barrier excluding bacteria from the epithelium. Bacterial penetration of this normally restricted zone is observed in many colitis models and also in patients with ulcerative colitis. Mucus defects that allow bacteria to reach the epithelium and to stimulate an immune system response can lead to the development of intestinal inflammation. The current state of our knowledge concerning the function of the mucus layers and the main mucin component, MUC2, in inflammatory bowel disease is described in this review.
MeSH term(s)	Animals ; Humans ; Inflammatory Bowel Diseases/metabolism ; Inflammatory Bowel Diseases/pathology ; Mucous Membrane/pathology ; Mucus/metabolism
Language	English
Publishing date	2014-04-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1340971-2
ISSN	1536-4844 ; 1078-0998
ISSN (online)	1536-4844
ISSN	1078-0998
DOI	10.1097/MIB.0000000000000117
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Article ; Online: Pregnancy and childbirth outcomes in women with myeloproliferative neoplasms-a nationwide population-based study of 342 pregnancies in Sweden.

Landtblom, Anna Ravn / Andersson, Therese M-L / Johansson, Anna L V / Wendel, Sophia Brismar / Lundberg, Frida E / Samuelsson, Jan / Björkholm, Magnus / Hultcrantz, Malin

Leukemia

2022 Volume 36, Issue 10, Page(s) 2461–2467

Abstract: Pregnancy and childbirth in women with myeloproliferative neoplasms (MPN) are reported to be associated with maternal thrombosis, hemorrhage, and placental dysfunction. To assess the risks of adverse events in pregnancy in women with MPN, we performed a ... ...

Abstract	Pregnancy and childbirth in women with myeloproliferative neoplasms (MPN) are reported to be associated with maternal thrombosis, hemorrhage, and placental dysfunction. To assess the risks of adverse events in pregnancy in women with MPN, we performed a large population-based study using Swedish health care registers, and included all pregnancies that had reached gestational week 22 (prior to 2008, week 28) during the years 1973-2017 in women with MPN. Control pregnancies were matched 1:1 for age, calendar year, and parity. We identified 342 pregnancies in 229 women with MPN. Preterm birth was significantly increased in pregnancies in MPN, 14% compared to 4% of pregnancies in controls (p < 0.001). Correspondingly, low birth weight (<2500 g) was also significantly increased in MPN pregnancies (p = 0.042). Stillbirth was rare, with two events (0.6%) in MPN, none in controls. Maternal thrombotic complications occurred in three (1%) of the pregnancies in MPN patients, compared to none in controls. Pregnancy-related bleeding affected 14% of pregnancies in MPN and 9% in controls (p < 0.110). Cesarean section was significantly more common in pregnancies in MPN. Incidence was 12.2 per 100.000 pregnancies. In summary, preterm birth was an important complication in MPN pregnancies, while maternal complications were less common than previously reported.
MeSH term(s)	Cesarean Section ; Female ; Humans ; Infant, Newborn ; Myeloproliferative Disorders/epidemiology ; Neoplasms ; Placenta ; Pregnancy ; Pregnancy Outcome/epidemiology ; Premature Birth/epidemiology ; Sweden/epidemiology
Language	English
Publishing date	2022-09-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-022-01688-w
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