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1.	Gustafsson, Jenny K, 1981, et al. (författare) Intestinal goblet cells sample and deliver lumenal antigens by regulated endocytic uptake and transcytosis 2021 Ingår i: eLife. - 2050-084X. ; 10 Tidskriftsartikel (refereegranskat)abstract Intestinal goblet cells maintain the protective epithelial barrier through mucus secretion and yet sample lumenal substances for immune processing through formation of goblet cell associated antigen passages (GAPs). The cellular biology of GAPs and how these divergent processes are balanced and regulated by goblet cells remains unknown. Using high-resolution light and electron microscopy, we found that in mice, GAPs were formed by an acetylcholine (ACh)-dependent endocytic event remarkable for delivery of fluid-phase cargo retrograde into the trans-golgi network and across the cell by transcytosis - in addition to the expected transport of fluid-phase cargo by endosomes to multi-vesicular bodies and lysosomes. While ACh also induced goblet cells to secrete mucins, ACh-induced GAP formation and mucin secretion were functionally independent and mediated by different receptors and signaling pathways, enabling goblet cells to differentially regulate these processes to accommodate the dynamically changing demands of the mucosal environment for barrier maintenance and sampling of lumenal substances. eLife digest Cells in the gut need to be protected against the many harmful microbes which inhabit this environment. Yet the immune system also needs to 'keep an eye' on intestinal contents to maintain tolerance to innocuous substances, such as those from the diet. The 'goblet cells' that are part of the gut lining do both: they create a mucus barrier that stops germs from invading the body, but they also can pass on molecules from the intestine to immune cells deep in the tissue to promote tolerance. This is achieved through a 'GAP' mechanism. A chemical messenger called acetylcholine can trigger both mucus release and the GAP process in goblet cells. Gustafsson et al. investigated how the cells could take on these two seemingly opposing roles in response to the same signal. A fluorescent molecule was introduced into the intestines of mice, and monitored as it pass through the goblet cells. This revealed how the GAP process took place: the cells were able to capture molecules from the intestines, wrap them in internal sack-like vesicles and then transport them across the entire cell. To explore the role of acetylcholine, Gustafsson et al. blocked the receptors that detect the messenger at the surface of goblet cells. Different receptors and therefore different cascades of molecular events were found to control mucus secretion and GAP formation; this explains how the two processes can be performed in parallel and independently from each other. Understanding how cells relay molecules to the immune system is relevant to other tissues in contact with the environment, such as the eyes, the airways, or the inside of the genital and urinary tracts. Understanding, and then ultimately harnessing this mechanism could help design of new ways to deliver drugs to the immune system and alter immune outcomes.
2.	Knoop, K. A., et al. (författare) In vivo labeling of epithelial cell-associated antigen passages in the murine intestine 2020 Ingår i: Lab Animal. - : Springer Science and Business Media LLC. - 0093-7355 .- 1548-4475. ; 49, s. 79-88 Tidskriftsartikel (refereegranskat)abstract Goblet cell-associated antigen passages can deliver luminal substances to antigen-presenting cells to induce antigen-specific T cell responses. This protocol describes how to identify and quantify intestinal epithelial cells that have the capacity to take up luminal substances, by intraluminal injection of fluorescent dextran, tissue sectioning for slide preparation and imaging with fluorescence microscopy. The intestinal immune system samples luminal contents to induce adaptive immune responses that include tolerance in the steady state and protective immunity during infection. How luminal substances are delivered to the immune system has not been fully investigated. Goblet cells have an important role in this process by delivering luminal substances to the immune system through the formation of goblet cell-associated antigen passages (GAPs). Soluble antigens in the intestinal lumen are transported across the epithelium transcellularly through GAPs and delivered to dendritic cells for presentation to T cells and induction of immune responses. GAPs can be identified and quantified by using the ability of GAP-forming goblet cells to take up fluorescently labeled dextran. Here, we describe a method to visualize GAPs and other cells that have the capacity to take up luminal substances by intraluminal injection of fluorescent dextran in mice under anesthesia, tissue sectioning for slide preparation and imaging with fluorescence microscopy. In contrast to in vivo two-photon imaging previously used to identify GAPs, this technique is not limited by anatomical constraints and can be used to visualize GAP formation throughout the length of the intestine. In addition, this method can be combined with common immunohistochemistry protocols to visualize other cell types. This approach can be used to compare GAP formation following different treatments or changes to the luminal environment and to uncover how sampling of luminal substances is altered in pathophysiological conditions. This protocol requires 8 working hours over 2-3 d to be completed.
3.	Knoop, K. A., et al. (författare) Synchronization of mothers and offspring promotes tolerance and limits allergy 2020 Ingår i: JCI insight. - : American Society for Clinical Investigation. - 2379-3708. ; 5:15 Tidskriftsartikel (refereegranskat)abstract Allergic disorders, characterized by Th2 immune responses to environmental substances, are increasingly common in children in Western societies. Multiple studies indicate that breastfeeding, early complementary introduction of food allergens, and antibiotic avoidance in the first year of life reduces allergic outcomes in at-risk children. Why the benefit of these practices is restricted to early life is largely unknown. We identified a preweaning interval during which dietary antigens are assimilated by the colonic immune system. This interval is under maternal control via temporal changes in breast milk, coincides with an influx of naive T cells into the colon, and is followed by the development of a long-lived population of colonic peripherally derived Tregs (pTregs) that can be specific for dietary antigens encountered during this interval. Desynchronization of mothers and offspring produced durable deficits in these pTregs, impaired tolerance to dietary antigens introduced during and after this preweaning interval, and resulted in spontaneous Th2 responses. These effects could be rescued by pTregs from the periweaning colon or by Tregs generated in vitro using periweaning colonic antigen-presenting cells. These findings demonstrate that mothers and their offspring are synchronized for the development of a balanced immune system.
4.	Gustafsson, Jenny K, 1981, et al. (författare) Carbachol-induced colonic mucus formation requires transport via NKCC1, K(+) channels and CFTR. 2015 Ingår i: Pflugers Archiv : European journal of physiology. - : Springer Science and Business Media LLC. - 1432-2013 .- 0031-6768. ; 467:7, s. 1403-1415 Tidskriftsartikel (refereegranskat)abstract The colonic mucosa protects itself from the luminal content by secreting mucus that keeps the bacteria at a distance from the epithelium. For this barrier to be effective, the mucus has to be constantly replenished which involves exocytosis and expansion of the secreted mucins. Mechanisms involved in regulation of mucus exocytosis and expansion are poorly understood, and the aim of this study was to investigate whether epithelial anion secretion regulates mucus formation in the colon. The muscarinic agonist carbachol was used to induce parallel secretion of anions and mucus, and by using established inhibitors of ion transport, we studied how inhibition of epithelial transport affected mucus formation in mouse colon. Anion secretion and mucin exocytosis were measured by changes in membrane current and epithelial capacitance, respectively. Mucus thickness measurements were used to determine the carbachol effect on mucus growth. The results showed that the carbachol-induced increase in membrane current was dependent on NKCC1 co-transport, basolateral K(+) channels and Cftr activity. In contrast, the carbachol-induced increase in capacitance was partially dependent on NKCC1 and K(+) channel activity, but did not require Cftr activity. Carbachol also induced an increase in mucus thickness that was inhibited by the NKCC1 blocker bumetanide. However, mice that lacked a functional Cftr channel did not respond to carbachol with an increase in mucus thickness, suggesting that carbachol-induced mucin expansion requires Cftr channel activity. In conclusion, these findings suggest that colonic epithelial transport regulates mucus formation by affecting both exocytosis and expansion of the mucin molecules.
5.	Gustafsson, Jenny K, 1981, et al. (författare) Dynamic changes in mucus thickness and ion secretion during Citrobacter rodentium infection and clearance. 2013 Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12 Tidskriftsartikel (refereegranskat)abstract Citrobacter rodentium is an attaching and effacing pathogen used as a murine model for enteropathogenic Escherichia coli. The mucus layers are a complex matrix of molecules, and mucus swelling, hydration and permeability are affected by many factors, including ion composition. Here, we used the C. rodentium model to investigate mucus dynamics during infection. By measuring the mucus layer thickness in tissue explants during infection, we demonstrated that the thickness changes dynamically during the course of infection and that its thickest stage coincides with the start of a decrease of bacterial density at day 14 after infection. Although quantitative PCR analysis demonstrated that mucin mRNA increases during early infection, the increased mucus layer thickness late in infection was not explained by increased mRNA levels. Proteomic analysis of mucus did not demonstrate the appearance of additional mucins, but revealed an increased number of proteins involved in defense responses. Ussing chamber-based electrical measurements demonstrated that ion secretion was dynamically altered during the infection phases. Furthermore, the bicarbonate ion channel Bestrophin-2 mRNA nominally increased, whereas the Cftr mRNA decreased during the late infection clearance phase. Microscopy of Muc2 immunostained tissues suggested that the inner striated mucus layer present in the healthy colon was scarce during the time point of most severe infection (10 days post infection), but then expanded, albeit with a less structured appearance, during the expulsion phase. Together with previously published literature, the data implies a model for clearance where a change in secretion allows reformation of the mucus layer, displacing the pathogen to the outer mucus layer, where it is then outcompeted by the returning commensal flora. In conclusion, mucus and ion secretion are dynamically altered during the C. rodentium infection cycle.
6.	Johansson, Malin E V, 1971, et al. (författare) Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. 2014 Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 63:2, s. 281-291 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: The inner mucus layer in mouse colon normally separates bacteria from the epithelium. Do humans have a similar inner mucus layer and are defects in this mucus layer a common denominator for spontaneous colitis in mice models and ulcerative colitis (UC)? METHODS AND RESULTS: The colon mucus layer from mice deficient in Muc2 mucin, Core 1 O-glycans, Tlr5, interleukin 10 (IL-10) and Slc9a3 (Nhe3) together with that from dextran sodium sulfate-treated mice was immunostained for Muc2, and bacterial localisation in the mucus was analysed. All murine colitis models revealed bacteria in contact with the epithelium. Additional analysis of the less inflamed IL-10(-/-) mice revealed a thicker mucus layer than wild-type, but the properties were different, as the inner mucus layer could be penetrated both by bacteria in vivo and by fluorescent beads the size of bacteria ex vivo. Clear separation between bacteria or fluorescent beads and the epithelium mediated by the inner mucus layer was also evident in normal human sigmoid colon biopsy samples. In contrast, mucus on colon biopsy specimens from patients with UC with acute inflammation was highly penetrable. Most patients with UC in remission had an impenetrable mucus layer similar to that of controls. CONCLUSIONS: Normal human sigmoid colon has an inner mucus layer that is impenetrable to bacteria. The colon mucus in animal models that spontaneously develop colitis and in patients with active UC allows bacteria to penetrate and reach the epithelium. Thus colon mucus properties can be modulated, and this suggests a novel model of UC pathophysiology.
7.	Johansson, Malin E V, 1971, et al. (författare) Composition and functional role of the mucus layers in the intestine. 2011 Ingår i: Cellular and Molecular Life Sciences. - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 68, s. 3635-3641 Forskningsöversikt (refereegranskat)abstract In discussions on intestinal protection, the protective capacity of mucus has not been very much considered. The progress in the last years in understanding the molecular nature of mucins, the main building blocks of mucus, has, however, changed this. The intestinal enterocytes have their apical surfaces covered by transmembrane mucins and the whole intestinal surface is further covered by mucus, built around the gel-forming mucin MUC2. The mucus of the small intestine has only one layer, whereas the large intestine has a two-layered mucus where the inner, attached layer has a protective function for the intestine, as it is impermeable to the luminal bacteria.
8.	Pelaseyed, Thaher, 1979, et al. (författare) Carbachol-induced MUC17 endocytosis is concomitant with NHE3 internalization and CFTR membrane recruitment in enterocytes. 2013 Ingår i: American journal of physiology. Cell physiology. - : American Physiological Society. - 1522-1563 .- 0363-6143. ; 305:4 Tidskriftsartikel (refereegranskat)abstract We have reported that transmembrane mucin MUC17 binds PDZ protein PDZK1, which retains MUC17 apically in enterocytes. MUC17 and transmembrane mucins MUC3 and MUC12 are suggested to build the enterocyte apical glycocalyx. Carbachol (CCh) stimulation of the small intestine results in gel-forming mucin secretion from goblet cells, something that requires adjacent enterocytes to secrete chloride and bicarbonate for proper mucin formation. Surface labeling and confocal imaging demonstrated that apically expressed MUC17 in Caco-2 cells and Muc3(17) in murine enterocytes were endocytosed upon stimulation with CCh. Relocation of MUC17 in response to CCh was specific as MUC3 and MUC12 did not relocate following CCh stimulation. MUC17 colocalized with PDZK1 under basal conditions, while MUC17 relocated to the terminal web and into early endosomes after CCh stimulation. CCh stimulation concomitantly internalized the Na(+/)H(+) exchanger 3 (NHE3) and recruited cystic fibrosis transmembrane conductance regulator (CFTR) to the apical membranes, a process that was important for CFTR-mediated bicarbonate secretion necessary for proper gel-forming mucin unfolding. The reason for the specific internalization of MUC17 is not understood, but it could limit the diffusion barrier for ion secretion caused by the apical enterocyte glycocalyx or alternatively act to sample luminal bacteria. Our results reveal well-orchestrated mucus secretion and trafficking of ion channels and the MUC17 mucin.
9.	Pelaseyed, Thaher, 1979, et al. (författare) The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system 2014 Ingår i: Immunological Reviews. - : Wiley. - 0105-2896 .- 1600-065X. ; 260:1, s. 8-20 Forskningsöversikt (refereegranskat)abstract The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins MUC2 and MUC5AC are the major components of the mucus in the intestine and stomach, respectively. In the small intestine, mucus limits the number of bacteria that can reach the epithelium and the Peyer's patches. In the large intestine, the inner mucus layer separates the commensal bacteria from the host epithelium. The outer colonic mucus layer is the natural habitat for the commensal bacteria. The intestinal goblet cells secrete not only the MUC2 mucin but also a number of typical mucus components: CLCA1, FCGBP, AGR2, ZG16, and TFF3. The goblet cells have recently been shown to have a novel gate-keeping role for the presentation of oral antigens to the immune system. Goblet cells deliver small intestinal luminal material to the lamina propria dendritic cells of the tolerogenic CD103+ type. In addition to the gel-forming mucins, the transmembrane mucins MUC3, MUC12, and MUC17 form the enterocyte glycocalyx that can reach about a micrometer out from the brush border. The MUC17 mucin can shuttle from a surface to an intracellular vesicle localization, suggesting that enterocytes might control and report epithelial microbial challenge. There is communication not only from the epithelial cells to the immune system but also in the opposite direction. One example of this is IL10 that can affect and improve the properties of the inner colonic mucus layer. The mucus and epithelial cells of the gastrointestinal tract are the primary gate keepers and controllers of bacterial interactions with the host immune system, but our understanding of this relationship is still in its infancy.
10.	Sharba, Sinan, et al. (författare) Interleukin 4 induces rapid mucin transport, increases mucus thickness and quality and decreases colitis and Citrobacter rodentium in contact with epithelial cells 2019 Ingår i: Virulence. - : Informa UK Limited. - 2150-5594 .- 2150-5608. ; 10:1, s. 97-117 Tidskriftsartikel (refereegranskat)abstract Citrobacter rodentium infection is a murine model for pathogenic intestinal Escherichia coli infection. C. rodentium infection causes an initial decrease in mucus layer thickness, followed by an increase during clearance. We aimed to identify the cause of these changes and to utilize this naturally occurring mucus stimulus to decrease pathogen impact and inflammation. We identified that mucin production and speed of transport from Golgi to secretory vesicles at the apical surface increased concomitantly with increased mucus thickness. Of the cytokines differentially expressed during increased mucus thickness, IFN-gamma and TNF-alpha decreased the mucin production and transport speed, whereas IL-4, IL-13, C. rodentium and E. coli enhanced these aspects. IFN-gamma and TNF-alpha treatment in combination with C. rodentium and pathogenic E. coli infection negatively affected mucus parameters in vitro, which was relieved by IL-4 treatment. The effect of IL-4 was more pronounced than that of IL-13, and in wild type mice, only IL-4 was present. Increased expression of Il-4, Il-4-receptor alpha, Stat6 and Spdef during clearance indicate that this pathway contributes to the increase in mucin production. In vivo IL-4 administration initiated 10 days after infection increased mucus thickness and quality and decreased colitis and pathogen contact with the epithelium. Thus, during clearance of infection, the concomitant increase in IL-4 protects and maintains goblet cell function against the increasing levels of TNF-alpha and IFN-gamma. Furthermore, IL-4 affects intestinal mucus production, pathogen contact with the epithelium and colitis. IL-4 treatment may thus have therapeutic benefits for mucosal healing.
11.	Ambort, Daniel, 1978, et al. (författare) Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin. 2012 Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 109:15, s. 5645-50 Tidskriftsartikel (refereegranskat)abstract MUC2, the major colonic mucin, forms large polymers by N-terminal trimerization and C-terminal dimerization. Although the assembly process for MUC2 is established, it is not known how MUC2 is packed in the regulated secretory granulae of the goblet cell. When the N-terminal VWD1-D2-D'D3 domains (MUC2-N) were expressed in a goblet-like cell line, the protein was stored together with full-length MUC2. By mimicking the pH and calcium conditions of the secretory pathway we analyzed purified MUC2-N by gel filtration, density gradient centrifugation, and transmission electron microscopy. At pH 7.4 the MUC2-N trimer eluted as a single peak by gel filtration. At pH 6.2 with Ca(2+) it formed large aggregates that did not enter the gel filtration column but were made visible after density gradient centrifugation. Electron microscopy studies revealed that the aggregates were composed of rings also observed in secretory granulae of colon tissue sections. The MUC2-N aggregates were dissolved by removing Ca(2+) and raising pH. After release from goblet cells, the unfolded full-length MUC2 formed stratified layers. These findings suggest a model for mucin packing in the granulae and the mechanism for mucin release, unfolding, and expansion.
12.	Ambort, Daniel, 1978, et al. (författare) Perspectives on mucus properties and formation--lessons from the biochemical world. 2012 Ingår i: Cold Spring Harbor perspectives in medicine. - : Cold Spring Harbor Laboratory. - 2157-1422. ; 2:11 Forskningsöversikt (refereegranskat)abstract Our model of the MUC2 mucin shows a well-organized netlike gel that is cross-linked by six different covalent and noncovalent bonds. When the MUC2 mucin is packed in the mucin granule it is organized by an amino-terminal concatenated ring platform formed at high calcium and low pH. This packing allows an ordered release and a normal mucin expansion when calcium is removed and pH increased by bicarbonate. This process is defective in the absence of cystic fibrosis transmembrane conductance regulator (CFTR)-dependent bicarbonate transport. The expanded secreted mucin is suggested to be self-organizing by properties inherited in the MUC2 mucin and by proteolytic processes.
13.	Birchenough, George M. H., et al. (författare) New developments in goblet cell mucus secretion and function 2015 Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 8:4, s. 712-719 Forskningsöversikt (refereegranskat)abstract Goblet cells and their main secretory product, mucus, have long been poorly appreciated; however, recent discoveries have changed this and placed these cells at the center stage of our understanding of mucosal biology and the immunology of the intestinal tract. The mucus system differs substantially between the small and large intestine, although it is built around MUC2 mucin polymers in both cases. Furthermore, that goblet cells and the regulation of their secretion also differ between these two parts of the intestine is of fundamental importance for a better understanding of mucosal immunology. There are several types of goblet cell that can be delineated based on their location and function. The surface colonic goblet cells secrete continuously to maintain the inner mucus layer, whereas goblet cells of the colonic and small intestinal crypts secrete upon stimulation, for example, after endocytosis or in response to acetyl choline. However, despite much progress in recent years, our understanding of goblet cell function and regulation is still in its infancy.
14.	Ermund, Anna, et al. (författare) Hyper-osmolarity and calcium chelation: Effects on cystic fibrosis mucus 2015 Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 764, s. 109-117 Tidskriftsartikel (refereegranskat)abstract A non-functional Cystic Fibrosis Transmembrane conductance Regulator (CFTR) leads to the disease cystic fibrosis (CF). Although the CFTR is expressed in multiple organs, pulmonary disease is the major cause of illness and death in patients with CF. Stagnant mucus, causing airway obstruction, bacterial overgrowth, persistent inflammation and tissue destruction characterizes the disease, but how the defect in CFTR function is coupled to the mucus phenotype is still controversial. We have recently shown that bicarbonate ions passing through CFTR are necessary for proper unfolding of the MUC2 mucin, thus highlighting the importance of bicarbonate ion transport via the CFTR and the ability of these ions to raise the pH and chelate calcium bound to the mucin as the important steps in forming normal mucus. In order to find potential CF treatments and expand our knowledge about the usefulness of bicarbonate as an active ingredient in formulations to alleviate mucus plugging, we used an Ussing-type chamber and explants from the F508del-CFTR mutant mouse ileum to test the effect of calcium chelators on mucus attachment, either in isolation or in combination with osmolytes such as mannitol or hypertonic saline. We found that increasing the concentration of bicarbonate, both alone or in combination with increased osmolarity of the solution, detached the otherwise attached CF mucus. (C) 2015 Elsevier B.V. All rights reserved.
15.	Ermund, Anna, et al. (författare) Mucus properties and goblet cell quantification in mouse, rat and human ileal Peyer's patches. 2013 Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12 Tidskriftsartikel (refereegranskat)abstract Peyer's patches (PPs) are collections of lymphoid follicles in the small intestine, responsible for scanning the intestinal content for foreign antigens such as soluble molecules, particulate matter as well as intact bacteria and viruses. The immune cells of the patch are separated from the intestinal lumen by a single layer of epithelial cells, the follicle-associated epithelium (FAE). This epithelium covers the dome of the follicle and contains enterocyte-like cells and M cells, which are particularly specialized in taking up antigens from the gut. However, the presence and number of goblet cells as well as the presence of mucus on top of the FAE is controversial. When mouse ileal PPs were mounted in a horizontal Ussing-type chamber, we could observe a continuous mucus layer at mounting and new, easily removable mucus was released from the villi on the patch upon stimulation. Confocal imaging using fluorescent beads revealed a penetrable mucus layer covering the domes. Furthermore, immunostaining of FAE from mice, rats and humans with a specific antibody against the main component of intestinal mucus, the MUC2 mucin, clearly identify mucin-containing goblet cells. Transmission electron micrographs further support the identification of mucus releasing goblet cells on the domes of PPs in these species.
16.	Ermund, Anna, et al. (författare) Studies of mucus in mouse stomach, small intestine, and colon. I. Gastrointestinal mucus layers have different properties depending on location as well as over the Peyer's patches. 2013 Ingår i: American journal of physiology. Gastrointestinal and liver physiology. - : American Physiological Society. - 1522-1547 .- 0193-1857. ; 305:5 Tidskriftsartikel (refereegranskat)abstract Colon has been shown to have a two-layered mucus system where the inner layer is devoid of bacteria. However, a complete overview of the mouse gastrointestinal mucus system is lacking. We now characterize mucus release, thickness, growth over time, adhesive properties, and penetrability to fluorescent beads from stomach to distal colon. Colon displayed spontaneous mucus release and all regions released mucus in response to carbachol and PGE2, except the distal colon and domes of Peyer's patches. Stomach and colon had an inner mucus layer that was adherent to the epithelium. In contrast, the small intestine and Peyer's patches had a single mucus layer that was easily aspirated. The inner mucus layer of the distal colon was not penetrable to beads the size of bacteria and the inner layer of the proximal colon was only partly penetrable. In contrast, the inner mucus layer of stomach was fully penetrable, as was the small intestinal mucus. This suggests a functional organization of the intestinal mucus system, where the small intestine has loose and penetrable mucus that may allow easy penetration of nutrients, in contrast to the stomach, where the mucus provides physical protection, and the colon, where the mucus separates bacteria from the epithelium. This knowledge of the mucus system and its organization improves our understanding of the gastrointestinal tract physiology.
17.	Gonzalez-Perez, V., et al. (författare) Goblet cell LRRC26 regulates BK channel activation and protects against colitis in mice 2021 Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 118:3 Tidskriftsartikel (refereegranskat)abstract Y Goblet cells (GCs) are specialized cells of the intestinal epithelium contributing critically to mucosal homeostasis. One of the functions of GCs is to produce and secrete MUC2, the mucin that forms the scaffold of the intestinal mucus layer coating the epithelium and separates the luminal pathogens and commensal microbiota from the host tissues. Although a variety of ion channels and transporters are thought to impact on MUC2 secretion, the specific cellular mechanisms that regulate GC function remain incompletely understood. Previously, we demonstrated that leucine-rich repeat-containing protein 26 (LRRC26), a known regulatory subunit of the Ca2+-and voltage-activated K+ channel (BK channel), localizes specifically to secretory cells within the intestinal tract. Here, utilizing a mouse model in which MUC2 is fluorescently tagged, thereby allowing visualization of single GCs in intact colonic crypts, we show that murine colonic GCs have functional LRRC26-associated BK channels. In the absence of LRRC26, BK channels are present in GCs, but are not activated at physiological conditions. In contrast, all tested MUC2(-) cells completely lacked BK channels. Moreover, LRRC26-associated BK channels underlie the BK channel contribution to the resting transepithelial current across mouse distal colonic mucosa. Genetic ablation of either LRRC26 or BK pore-forming alpha-subunit in mice results in a dramatically enhanced susceptibility to colitis induced by dextran sodium sulfate. These results demonstrate that normal potassium flux through LRRC26-associated BK channels in GCs has protective effects against colitis in mice.
18.	Gustafsson, Jenny K, 1981, et al. (författare) An ex vivo method for studying mucus formation, properties and thickness in human colonic biopsies and mouse small and large intestinal explants. 2012 Ingår i: American journal of physiology. Gastrointestinal and liver physiology. - : American Physiological Society. - 1522-1547 .- 0193-1857. ; 302:4, s. 430-438 Tidskriftsartikel (refereegranskat)abstract The colon mucus layers minimize the contact between the luminal flora and the epithelial cells and defects in this barrier may lead to colonic inflammation. We now describe an ex vivo method for analysis of mucus properties in human colon and mouse small and large intestine. Materials and methods: Intestinal explants were mounted in horizontal perfusion chambers. The mucus surface was visualized by adding charcoal particles on the apical side and mucus thickness was measured using a micropipette. Mucus thickness, adhesion and growth rate was recorded for 1 h. In mouse and human colon, the ability of the mucus to act as a barrier to beads the size of bacteria was also evaluated. Tissue viability was monitored by transepithelial potential difference. Results: In mouse ileum the mucus could be removed by gentle aspiration, whereas in colon about 40 µm of the mucus remained attached to the epithelial surface. Both mouse and human colon had an inner mucus layer that was not penetrated by the fluorescent beads. Spontaneous mucus growth was observed in human (240 µm/h) and mouse (100 µm/h) colon, but not in mouse ileum. In contrast, stimulation with carbachol induced a higher mucus secretion in ileum than colon (mouse ileum: Δ200 μm, mouse colon: Δ130 µm, human colon: Δ140 μm). In conclusion, while retaining key properties from the mucus system in vivo, this set up also allows for studies of the highly dynamic mucus system under well controlled conditions.
19.	Gustafsson, Jenny K, 1981, et al. (författare) Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype. 2012 Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 209:7, s. 1263-72 Tidskriftsartikel (refereegranskat)abstract Cystic fibrosis (CF) is caused by a nonfunctional chloride and bicarbonate ion channel (CF transmembrane regulator [CFTR]), but the link to the phenomenon of stagnant mucus is not well understood. Mice lacking functional CFTR (CftrΔ508) have no lung phenotype but show similar ileal problems to humans. We show that the ileal mucosa in CF have a mucus that adhered to the epithelium, was denser, and was less penetrable than that of wild-type mice. The properties of the ileal mucus of CF mice were normalized by secretion into a high concentration sodium bicarbonate buffer (~100 mM). In addition, bicarbonate added to already formed CF mucus almost completely restored the mucus properties. This knowledge may provide novel therapeutic options for CF.
20.	Gustafsson, Jenny K, 1981 (författare) Colonic barrier function in ulcerative colitis - Interactions between ion and mucus secretion 2012 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Anion and mucus secretions have traditionally been looked upon as two separate parts of the epithelial defense system. The importance of anion secretion has been attributed to its role in creating the driving force for fluid secretion that flushes the epithelium from bacteria, while mucus secretion ensures protection via the mucus layer that forms a physical barrier between the bacteria and the epithelium. In addition to its role in fluid secretion it is becoming increasingly clear that anion secretion contributes to the regulation of mucus properties. This opens up for the possibility that alterations in epithelial transport can regulate the colonic barrier also via its effects on the mucus layer. The aim of the present thesis was to clarify how epithelial anion secretion regulates the intestinal mucus layer, and to delineate how these two systems are affected in Ulcerative colitis, the most common chronic inflammatory bowel disease. By using an in house developed ex vivo method for the study of mucus properties, it was shown that CFTR mediated bicarbonate secretion regulates many aspects of mucus properties in the mouse small intestine, including mucus growth, adherence and penetrability. In the colon, baseline mucus growth was CFTR independent whereas secretagogue (carbachol) induced mucus growth required a functioning CFTR channel. The impaired mucus growth seen in mice lacking a functional CFTR channel was probably not due to reduced mucus secretion since the exocytosis response to carbachol was unaffected. In WT colon, carbachol induced mucus exocytosis required functioning basolateral transport via NKCC1 and K+ channels. To test how epithelial transport and mucus properties were affect by inflammation, the barrier properties of the colonic mucus were studied in various murine colitis models (IL10-/-, TLR5-/-, NHE3-/-, C1GalT-/- and DSS induced colitis) and in UC patients. The results showed that all tested colitis models had signs of a defective mucus barrier, defined as abnormal amounts of bacteria in contact with the epithelium. Alterations in the mucus layer were also found in the human colon. Colonic biopsies from control patients secreted mucus that separated beads the size of bacteria from the epithelium, whereas biopsies from UC patients with acute disease secreted mucus that was penetrable to the beads. The majority of UC patients in remission secreted mucus with normal penetrability, while a subset of patients secreted mucus that was permeable to the beads. Also epithelial anion secretion was normal in the distal colon of UC patients in remission, but in the proximal colon the reactivity to secretagogues was shifted towards an increased forskolin response and a decreased carbachol response. In summary, the results from this thesis show that acute colitis makes the colonic mucus layer unable to physically separate bacteria from the epithelium. In the small intestine, CFTR mediated secretion regulates most aspect of mucus properties while in the colon only secretagogue-induced mucus growth seems to be CFTR dependent. In ulcerative colitis in remission, the epithelium of the proximal colon becomes more reactive to stimulation of the CFTR system, which may be a defense mechanism to reduce the degree of contact between bacteria and epithelium.
21.	Gustafsson, Jenny K, 1981, et al. (författare) Ex vivo measurements of mucus secretion by colon explants. 2012 Ingår i: Methods in Molecular Biology. - Totowa, NJ : Humana Press. - 1064-3745 .- 1940-6029. ; 842, s. 237-43 Tidskriftsartikel (refereegranskat)abstract An explant tissue system for the study and recording of mucus secretion has been developed. Human colon biopsies or tissue from experimental animals are mounted in a horizontal perfusion chamber and the mucus accumulated on the apical side is observed and measured.
22.	Gustafsson, Jenny K, 1981, et al. (författare) Response to 'Altered secretion in the right colon during ulcerative colitis: is it due to disease or to 5-ASA?'. 2013 Ingår i: Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society. - : Wiley. - 1365-2982. ; 25:5 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
23.	Gustafsson, Jenny K, 1981, et al. (författare) The role of goblet cells and mucus in intestinal homeostasis 2022 Ingår i: Nature Reviews Gastroenterology & Hepatology. - : Springer Science and Business Media LLC. - 1759-5045 .- 1759-5053. ; 19, s. 785-803 Forskningsöversikt (refereegranskat)abstract Mucus, produced by goblet cells, provides the intestinal tract with an additional layer of protection. This Review discusses the role of mucus and goblet cells in intestinal health and disease, and dissects the underlying regulatory mechanisms. 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.
24.	Gustafsson, Jenny K, 1981, et al. (författare) Ulcerative colitis patients in remission have an altered secretory capacity in the proximal colon despite macroscopically normal mucosa 2012 Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925. ; 24:8 Tidskriftsartikel (refereegranskat)abstract Background One of the hallmarks of acute colitis is loss of epithelial transport. For unknown reasons, many patients still suffer from GI symptoms during remission, indicating a sustained imbalance between absorption and secretion. We hypothesize that the colonic epithelium becomes more reactive to secretagogues to compensate for a failing barrier. Methods Biopsies from ascending colon and sigmoid colon of UC patients in remission and controls were mounted in Ussing chambers. Membrane current (Im) and epithelial capacitance (Cp) were used as markers for anion secretion and mucus exocytosis. Carbachol (1 mmol L-1) and forskolin (10 mu mol L-1) were used to study Ca2+ and cAMP-mediated secretion. Key Results Baseline values showed segmental patterns with higher Im in ascending colon and higher Cp in sigmoid colon of both UC patients and controls, but the patterns did not differ between the groups. The Im response to forskolin was increased (+35%) in the ascending colon of UC patients and the Im response to carbachol was decreased (-40%) in the same segment. No group differences were seen in the distal colon for either the forskolin or carbachol-induced Im responses. The Cp response to carbachol was instead up-regulated in the distal colon of UC patients, but remained unaffected in the proximal colon. Conclusions & Inferences The proximal colonic mucosa of UC patients in remission seems to shift its reactivity to secretagogues, becoming more sensitive to cAMP-dependent secretion and less sensitive to Ca2+-dependent secretion. This phenomenon may contribute to residual diarrhea in this patient group, despite resolution of inflammation.
25.	Johansson, Malin E V, 1971, et al. (författare) Bacteria penetrate the inner mucus layer before inflammation in the dextran sulfate colitis model. 2010 Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 5:8 Tidskriftsartikel (refereegranskat)abstract Protection of the large intestine with its enormous amount of commensal bacteria is a challenge that became easier to understand when we recently could describe that colon has an inner attached mucus layer devoid of bacteria (Johansson et al. (2008) Proc. Natl. Acad. Sci. USA 105, 15064-15069). The bacteria are thus kept at a distance from the epithelial cells and lack of this layer, as in Muc2-null mice, allow bacteria to contact the epithelium. This causes colitis and later on colon cancer, similar to the human disease Ulcerative Colitis, a disease that still lacks a pathogenetic explanation. Dextran Sulfate (DSS) in the drinking water is the most widely used animal model for experimental colitis. In this model, the inflammation is observed after 3-5 days, but early events explaining why DSS causes this has not been described.
26.	Ljungholm, Penny L., et al. (författare) The anion exchanger slc26a3 regulates colonic mucus expansion during steady state and in response to prostaglandin E2, while Cftr regulates de novo mucus release in response to carbamylcholine 2024 Ingår i: PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY. - 0031-6768 .- 1432-2013. Tidskriftsartikel (refereegranskat)abstract The intestinal epithelium is covered by mucus that protects the tissue from the luminal content. Studies have shown that anion secretion via the cystic fibrosis conductance regulator (Cftr) regulates mucus formation in the small intestine. However, mechanisms regulating mucus formation in the colon are less understood. The aim of this study was to explore the role of anion transport in the regulation of mucus formation during steady state and in response to carbamylcholine (CCh) and prostaglandin E-2 (PGE(2)). The broad-spectrum anion transport inhibitor 4,4 '-diisothiocyanatostilbene-2,2 '-disulfonate (DIDS), CftrdF508 (CF) mice, and the slc26a3 inhibitor SLC26A3-IN-2 were used to inhibit anion transport. In the distal colon, steady-state mucus expansion was reduced by SLC26A3-IN-2 and normal in CF mice. PGE(2) stimulated mucus expansion without de novo mucus release in wild type (WT) and CF colon via slc26a3 sensitive mechanisms, while CCh induced de novo mucus secretion in WT but not in CF colon. However, when added simultaneously, CCh and PGE(2) stimulated de novo mucus secretion in the CF colon via DIDS-sensitive pathways. A similar response was observed in CF ileum that responded to CCh and PGE(2) with DIDS-sensitive de novo mucus secretion. In conclusion, this study suggests that slc26a3 regulates colonic mucus expansion, while Cftr regulates CCh-induced de novo mucus secretion from ileal and distal colon crypts. Furthermore, these findings demonstrate that in the absence of a functional Cftr channel, parallel stimulation with CCh and PGE(2) activates additional anion transport processes that help release mucus from intestinal goblet cells.
27.	Pyko, Andrei, et al. (författare) Long-Term Exposure to Transportation Noise and Ischemic Heart Disease: A Pooled Analysis of Nine Scandinavian Cohorts. 2023 Ingår i: Environmental health perspectives. - : Environmental Health Perspectives. - 1552-9924 .- 0091-6765. ; 131:1 Tidskriftsartikel (refereegranskat)abstract Transportation noise may induce cardiovascular disease, but the public health implications are unclear.The study aimed to assess exposure-response relationships for different transportation noise sources and ischemic heart disease (IHD), including subtypes.Pooled analyses were performed of nine cohorts from Denmark and Sweden, together including 132,801 subjects. Time-weighted long-term exposure to road, railway, and aircraft noise, as well as air pollution, was estimated based on residential histories. Hazard ratios (HRs) were calculated using Cox proportional hazards models following adjustment for lifestyle and socioeconomic risk factors.A total of 22,459 incident cases of IHD were identified during follow-up from national patient and mortality registers, including 7,682 cases of myocardial infarction. The adjusted HR for IHD was 1.03 [95% confidence interval (CI) 1.00, 1.05] per 10 dB Lden for both road and railway noise exposure during 5 y prior to the event. Higher risks were indicated for IHD excluding angina pectoris cases, with HRs of 1.06 (95% CI: 1.03, 1.08) and 1.05 (95% CI: 1.01, 1.08) per 10 dB Lden for road and railway noise, respectively. Corresponding HRs for myocardial infarction were 1.02 (95% CI: 0.99, 1.05) and 1.04 (95% CI: 0.99, 1.08). Increased risks were observed for aircraft noise but without clear exposure-response relations. A threshold at around 55 dB Lden was suggested in the exposure-response relation for road traffic noise and IHD.Exposure to road, railway, and aircraft noise in the prior 5 y was associated with an increased risk of IHD, particularly after exclusion of angina pectoris cases, which are less well identified in the registries. https://doi.org/10.1289/EHP10745.
28.	Rodríguez-Piñeiro, Ana María, et al. (författare) Studies of mucus in mouse stomach, small intestine, and colon. II. Gastrointestinal mucus proteome reveals Muc2 and Muc5ac accompanied by a set of core proteins. 2013 Ingår i: American journal of physiology. Gastrointestinal and liver physiology. - : American Physiological Society. - 1522-1547 .- 0193-1857. ; 305:5 Tidskriftsartikel (refereegranskat)abstract The mucus that protects the surface of the gastrointestinal tract is rich in specialized O-glycoproteins called mucins, but little is known about other mucus proteins or their variability along the gastrointestinal tract. To ensure that only mucus was analyzed, we combined collection from explant tissues mounted in perfusion chambers, liquid sample preparation, single-shot mass spectrometry, and specific bioinformatics tools, to characterize the proteome of the murine mucus from stomach to distal colon. With our approach, we identified ∼1,300 proteins in the mucus. We found no differences in the protein composition or abundance between sexes, but there were clear differences in mucus along the tract. Noticeably, mucus from duodenum showed similarities to the stomach, probably reflecting the normal distal transport. Qualitatively, there were, however, fewer differences than might had been anticipated, suggesting a relatively stable core proteome (∼80% of the total proteins identified). Quantitatively, we found significant differences (∼40% of the proteins) that could reflect mucus specialization throughout the gastrointestinal tract. Hierarchical clustering pinpointed a number of such proteins that correlated with Muc2 (e.g., Clca1, Zg16, Klk1). This study provides a deeper knowledge of the gastrointestinal mucus proteome that will be important in further understanding this poorly studied mucosal protection system.
29.	Sadio, Ana, et al. (författare) Modified-chitosan/siRNA nanoparticles downregulate cellular CDX2 expression and cross the gastric mucus barrier. 2014 Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6 Tidskriftsartikel (refereegranskat)abstract Development of effective non-viral vectors is of crucial importance in the implementation of RNA interference in clinical routine. The localized delivery of siRNAs to the gastrointestinal mucosa is highly desired but faces specific problems such as the stability in gastric acidity conditions and the presence of the mucus barrier. CDX2 is a transcription factor critical for intestinal differentiation being involved in the initiation and maintenance of gastrointestinal diseases. Specifically, it is the trigger of gastric intestinal metaplasia which is a precursor lesion of gastric cancer. Its expression is also altered in colorectal cancer, where it may constitute a lineage-survival oncogene. Our main objective was to develop a nanoparticle-delivery system of siRNA targeting CDX2 using modified chitosan as a vector. CDX2 expression was assessed in gastric carcinoma cell lines and nanoparticles behaviour in gastrointestinal mucus was tested in mouse explants. We show that imidazole-modified chitosan and trimethylchitosan/siRNA nanoparticles are able to downregulate CDX2 expression and overpass the gastric mucus layer but not colonic mucus. This system might constitute a potential therapeutic approach to treat CDX2-dependent gastric lesions.
30.	Suriano, Francesco, 1987, et al. (författare) Diet, microbiota, and the mucus layer: The guardians of our health 2022 Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13 Forskningsöversikt (refereegranskat)abstract The intestinal tract is an ecosystem in which the resident microbiota lives in symbiosis with its host. This symbiotic relationship is key to maintaining overall health, with dietary habits of the host representing one of the main external factors shaping the microbiome-host relationship. Diets high in fiber and low in fat and sugars, as opposed to Western and high-fat diets, have been shown to have a beneficial effect on intestinal health by promoting the growth of beneficial bacteria, improve mucus barrier function and immune tolerance, while inhibiting pro-inflammatory responses and their downstream effects. On the contrary, diets low in fiber and high in fat and sugars have been associated with alterations in microbiota composition/functionality and the subsequent development of chronic diseases such as food allergies, inflammatory bowel disease, and metabolic disease. In this review, we provided an updated overview of the current understanding of the connection between diet, microbiota, and health, with a special focus on the role of Western and high-fat diets in shaping intestinal homeostasis by modulating the gut microbiota.

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