Mucin Secretion Research Articles

The regulatory role of SFRP5/WNT5A axis in allergic rhinitis through inhibiting JNK pathway activation and lowering mucin generation in human nasal epithelial cells

Allergic rhinitis (AR) is tightly associated with type 2 inflammation. SFRP5 combined with WNT5A mainly inhibits chronic inflammatory response, atherosclerosis, and other metabolic disorders. However, the effect of SFRP5/WNT5A axis on recombinant human interleukin-13 (rhIL-13)-induced inflammation has not been studied. In this study, we aimed to investigate whether secreted frizzled-related protein 5 (SFRP5) could modulate the production of cytokines relevant to eosinophil infiltration and mucin secretion through blocking the activation of Wnt family 5A (WNT5A) signaling pathway. A mouse model of AR demonstrated low expression of SFRP5 and high expression of WNT5A, and indicated that the number of eosinophil and goblet cells was increased, concomitant with elevated IL-13, colony stimulating factor 2 (CSF2), chemokine ligand 11 (CCL11), Mucin 4, and Mucin 5AC levels. Furthermore, lentivirus-SFRP5 overexpression up-regulated the expression of SFRP5 but down-regulated WNT5A level, and inhibited the activation of JNK pathway via decreasing p-JNK1/2 (Thr183/Tyr185) and p-c-Jun (Ser73) protein expressions in rhIL-13-treated human nasal epithelial cells (HNEpCs). Noticeably, SFRP5 overexpression markedly reduced rhIL-13-induced inflammatory protein and mucin generation through lowered CSF2, CCL11, Mucin 4, as well as Mucin 5AC levels. Taken together, these findings confirmed the regulatory role of SFRP5/WNT5A axis in rhIL-13-mediated inflammatory response in HNEpCs.

Dual role of eugenol on chronic gastric ulcer in rats: Low-dose healing efficacy and the worsening gastric lesion in high doses

This study evaluated the gastric healing activity of eugenol, the main bioactive compound from clove (Syzygium aromaticum) essential oil. Five groups of female Wistar rats were submitted to acetic acid-induced ulcer model and treated with Vehicle (1 ml/kg, p.o.), eugenol (1, 10 or 100 mg/kg, p.o) or omeprazole (20 mg/kg, p.o), twice a day, by seven or fourteen days. Macroscopic, microscopic, and biochemical analyses were performed in the ulcerated site. Eugenol (1 mg/kg, p.o) administered by 7 or 14 days accelerated the gastric healing process by 33% and 52%, respectively. The healing action of eugenol was accompanied by the rescue on the histological architecture and the normalization of the superoxide dismutase and catalase activity. Moreover, eugenol (1 mg/kg, p.o) reduced the gastric mucosal myeloperoxidase activity and increased the mucin secretion. In contrast, eugenol at a dose of 100 mg/kg administered by 7 days enhanced 49% the ulcerated area, but at 10 mg/kg did not change the ulcer area after 7 or 14 days of treatment. Thus, although the gastric healing potential of eugenol is evident, its administration needs to be manageable in an adequate dose due to the worsening of the gastric lesion with its use in high doses.

Pic Protein From Enteroaggregative E. coli Induces Different Mechanisms for Its Dual Activity as a Mucus Secretagogue and a Mucinase.

A hallmark of enteroaggregative Escherichia coli (EAEC) infection is the formation of an intestinal biofilm, which comprises a mucus layer with immersed bacteria. Pic is an autotransporter secreted by EAEC, and other E. coli pathotypes, and has been involved in two apparently contradictory phenotypes, as a mucus secretagogue and as a mucinase. Here, we investigated this Pic dual activity, mucus secretagogue capability and mucinolytic activity, in human goblet cells that secrete MUC2 and MUC5AC. Pic induced mucus hypersecretion directly in the goblet cells, without other intestinal cell types involved. At the same time, Pic exhibited strong proteolytic activity on the secreted mucins. These activities were independent since a mutation in the serine protease motif (PicS258I) abolished mucin degradation while maintaining the mucus secretagogue activity intact. Furthermore, deoxycholic acid (DCA)-induced mucins were proteolytically degraded when goblet cells were co-incubated with DCA/Pic, while co-incubation with DCA/PicS258I induced a synergistic effect on mucus hypersecretion. Pic was more efficient degrading MUC5AC than MUC2, but no degradation was detected with Pic inactivated at the active site by mutation or pharmacological inhibition. Remarkably, Pic cleaved MUC2 and MUC5AC in the C-terminal domain, leaving N-terminal subproducts, impacting the feature of gel-forming mucins and allowing mucus layer penetration by EAEC. Astonishingly, Pic stimulated rapid mucin secretion in goblet-like cells by activating the intracellular calcium pathway resulting from the PLC signal transduction pathway, leading to the production of DAG and releasing IP3, a second messenger of calcium signaling. Therefore, the dual activity of Pic, as a mucus secretagogue and a mucinase, is relevant in the context of carbon source generation and mucus layer penetration, allowing EAEC to live within the layer of mucus but also access epithelial cells.

The Lumen of Human Intestinal Organoids Poses Greater Stress to Bacteria Compared to the Germ-Free Mouse Intestine: Escherichia coli Deficient in RpoS as a Colonization Probe.

Pluripotent stem-cell-derived human intestinal organoids (HIOs) are three-dimensional, multicellular structures that model a naive intestinal epithelium in an in vitro system. Several published reports have investigated the use of HIOs to study host-microbe interactions. We recently demonstrated that microinjection of the nonpathogenic Escherichia coli strain ECOR2 into HIOs induced morphological and functional maturation of the HIO epithelium, including increased secretion of mucins and cationic antimicrobial peptides. In the current work, we use ECOR2 as a biological probe to further characterize the environment present in the HIO lumen. We generated an isogenic mutant in the general stress response sigma factor RpoS and employed this mutant to compare challenges faced by a bacterium during colonization of the HIO lumen relative to the germ-free mouse intestine. We demonstrate that the loss of RpoS significantly decreases the ability of ECOR2 to colonize HIOs, although it does not prevent colonization of germ-free mice. These results indicate that the HIO lumen is a more restrictive environment to E. coli than the germ-free mouse intestine, thus increasing our understanding of the HIO model system as it pertains to studying the establishment of intestinal host-microbe symbioses.IMPORTANCE Technological advancements have driven and will continue to drive the adoption of organotypic systems for investigating host-microbe interactions within the human intestinal ecosystem. Using E. coli deficient in the RpoS-mediated general stress response, we demonstrate that the type or severity of microbial stressors within the HIO lumen is more restrictive than those of the in vivo environment of the germ-free mouse gut. This study provides important insight into the nature of the HIO microenvironment from a microbiological standpoint.

Gene networks for three feed efficiency criteria reveal shared and specific biological processes

BackgroundFrench beef producers suffer from the decrease in profitability of their farms mainly because of the continuous increase in feed costs. Selection for feed efficiency in beef cattle represents a relevant solution to face this problem. However, feed efficiency is a complex trait that can be assessed by three major criteria: residual feed intake (RFI), residual gain (RG) and feed efficiency ratio (FE), which involve different genetic determinisms. An analysis that combines phenotype and whole-genome sequence data provides a unique framework for genomic studies. The aim of our study was to identify the gene networks and the biological processes that are responsible for the genetic determinism that is shared between these three feed efficiency criteria.ResultsA population of 1477 French Charolais young bulls was phenotyped for feed intake (FI), average daily gain (ADG) and final weight (FW) to estimate RFI, RG and FE. A subset of 789 young bulls was genotyped on the BovineSNP50 single nucleotide polymorphism (SNP) array and imputed at the sequence level using RUN6 of the 1000 Bull Genomes Project. We conducted a genome-wide association study (GWAS) to estimate the individual effect of 8.5 million SNPs and applied an association weight matrix (AWM) approach to analyse the results, one for each feed efficiency criterion. The results highlighted co-association networks including 626 genes for RFI, 426 for RG and 564 for FE. Enrichment assessment revealed the biological processes that show the strongest association with RFI, RG and FE, i.e. digestive tract (salivary, gastric and mucin secretion) and metabolic processes (cellular and cardiovascular). Energetic functions were more associated with RFI and FE and cardio-vascular and cellular processes with RG. Several hormones such as apelin, glucagon, insulin, aldosterone, the gonadotrophin releasing hormone and the thyroid hormone were also identified, and these should be tested in future studies as candidate biomarkers for feed efficiency.ConclusionsThe combination of network and pathway analyses at the sequence level led to the identification of both common and specific mechanisms that are involved in RFI, RG and FE, and to a better understanding of the genetic determinism underlying these three criteria. The effects of the genes involved in each of the identified processes need to be tested in genomic evaluations to confirm the potential gain in reliability of using functional variants to select animals for feed efficiency.

Alteration of mucins in the submandibular gland during aging in mice

ObjectiveMucins are large glycosylated glycoproteins that are produced in the salivary glands, and their changes may contribute to the development of xerostomia due to aging and the accompanying deterioration of oral hygiene. This study aimed to characterize the changes in the mucins produced in submandibular gland (SMG) during the aging process. MethodsSMG mucins derived from mice of each age were separated using supported molecular matrix electrophoresis (SMME). Subsequently, the membranes were stained with Alcian blue (AB) or blotted with MAL-II lectin. The SMME membranes stained with AB were subjected to densitometric analysis and glycan analysis. The detailed structures of O-glycan were investigated by tandem mass spectrometry (MS/MS). ResultsThe SMG of mice secreted three mucins with different glycan profiles: age-specific mucin, youth-specific mucin, and a mucin expressed throughout life, and the expression patterns of these mucins change during aging. Additionally, age-specific mucin began to be detected at about 12 months of age. A mucin expressed throughout life and age-specific mucin had the same mass of major glycans but different structures. Furthermore, the proportion of mucin glycan species expressed throughout life changed during the aging process, and aging tended to decrease the proportion of fucosylated glycans and increase the proportion of sialoglycans. ConclusionThere are three secretory mucins with different glycan profiles in the SMG of mice, and their expression patterns change according to the period of the aging process. The proportion of glycan species of mucin expressed throughout life also changes during the aging process.

Pharyngeal Deposits Comprising Salivary Mucin in Tube-fed Elderly Patients: MUC2 and MUC7 Immunoreactivity.

Several investigators have reported that oral membranous and pharyngeal viscous deposits developed in bedridden elderly persons requiring nursing care without oral intake. Therefore, this study aimed to clarify the origin of viscous deposits on the pharyngeal mucosa based on characteristics of salivary and tracheal secretory mucin. The participants were 35 elderly people who required nursing care. All 46 collected specimens, including 30 intraoral and 16 pharyngeal specimens, were stained against specific mucins secreted from the respiratory tract and saliva gland using antibodies anti-MUC2 and anti-MUC7, respectively. Out of 35 participants, the intraoral membranous deposits and deposits on the pharyngeal mucosa developed in 17 (48.6%) and 10 persons (28.6%), respectively. The pharyngeal deposits developed in 58.8% of participants who developed intraoral deposits. All pathological specimens shared microscopic findings of various combinations of eosinophilic lamellar structure and a pale-basophilic amorphous substance. Immunohistochemically, both the 30 oral and the 16 pharyngeal specimens obtained from 17 participants were consistently positive for MUC7 but negative for MUC2. In conclusion, we clarified that the mucoid component of both oral and pharyngeal deposits comprised MUC7 salivary mucin, which revealed that both deposits originated from the oral cavity. This result strongly suggests that oral care is intimately related to oral and pharyngeal conditions.

Menthol enhances interleukin-13-induced synthesis and secretion of mucin 5AC in human bronchial epithelial cells

To investigate the effect of interleukin (IL) -13 combined with cold stimulation on synthesis and secretion of mucin (MUC) 5AC in human bronchial epithelial cell line 16HBE and explore the role of transient receptor potential 8 (TRPM8) and anti-apoptotic factor B-cell lymphoblast-2 (Bcl-2) in this process. 16HBE cells were stimulated with 10 ng/mL IL-13, 1 mmol/L menthol, or both (1 mmol/L menthol was added after 6 days of IL-13 stimulation), and the changes in the expression of MUC5AC, intracellular Ca2+ concentration and Bcl-2 expression were evaluated. The effects of ABT-263 (a Bcl-2 inhibitor) and BCTC (a TRPM8 ion channel inhibitor), alone or in combination, on MUC5AC expression in the cells were tested, and the changes in intracellular Ca2+ and Bcl-2 expression following BCTC treatment were observed. The cell viability was assessed using CCK-8 assay, the mRNA expressions of MUC5AC and Bcl-2 were detected with real-time quantitative PCR, the level of MUC5AC in the culture medium was measured with ELISA, and the intracellular Ca2+ fluorescence intensity was determined with flow cytometry. The mRNA and protein expressions of MUC5AC increased significantly in 16HBE cells following stimulation with IL-13, menthol, and both (P < 0.05), and were the highest in the combined treatment group with its peak level occurred at 24 h (P < 0.01). The intracellular Ca2+ fluorescence intensity and Bcl-2 mRNA expression were also increased in 16HBE cells after the stimulations (P < 0.05), and the increments were the most obvious in the combined treatment group (P < 0.01). Treatment with BCTC significantly lowered intracellular Ca2+ fluorescence intensity and the expressions of Bcl-2 and MUC5AC mRNA and protein in the cells stimulated with menthol or with both IL-13 and menthol (P < 0.05), but caused no significant changes in IL-13-stimulated cells (P > 0.05). Treatment with ABT-263 significantly lowered the mRNA and protein expressions of MUC5AC in the cells stimulated with IL-13 and menthol either alone or in combination (P < 0.05). Menthol combined with IL-13 produces a synergistic effect to promote the synthesis and secretion of MUC5AC in 16HBE cells possibly by activating TRPM8 receptor to upregulate the expression of Bcl-2.

Unveiling the effect of dietary essential oils supplementation in Sparus aurata gills and its efficiency against the infestation by Sparicotyle chrysophrii

A microencapsulated feed additive composed by garlic, carvacrol and thymol essential oils (EOs) was evaluated regarding its protective effect in gills parasitized by Sparicotyle chrysophrii in Sparus aurata. A nutritional trial (65 days) followed by a cohabitation challenge with parasitized fish (39 days) were performed. Transcriptomic analysis by microarrays of gills of fish fed the EOs diet showed an up-regulation of genes related to biogenesis, vesicular transport and exocytosis, leukocyte-mediated immunity, oxidation–reduction and overall metabolism processes. The functional network obtained indicates a tissue-specific pro-inflammatory immune response arbitrated by degranulating acidophilic granulocytes, sustained by antioxidant and anti-inflammatory responses. The histochemical study of gills also showed an increase of carboxylate glycoproteins containing sialic acid in mucous and epithelial cells of fish fed the EOs diet, suggesting a mucosal defence mechanism through the modulation of mucin secretions. The outcomes of the in vivo challenge supported the transcriptomic results obtained from the nutritional trial, where a significant reduction of 78% in the abundance of S. chrysophrii total parasitation and a decrease in the prevalence of most parasitic developmental stages evaluated were observed in fish fed the EOs diet. These results suggest that the microencapsulation of garlic, carvacrol and thymol EOs could be considered an effective natural dietary strategy with antiparasitic properties against the ectoparasite S. chrysophrii.

The relationship between intestinal goblet cells and the immune response.

Goblet cells (GCs) are single-cell glands that produce and secrete mucin. Mucin forms a mucus layer, which can separate the materials in cavities from the intestinal epithelium and prevent the invasion of pathogenic microorganisms in various ways. GCs can also participate in the immune response through nonspecific endocytosis and goblet cell-associated antigen passages (GAPs). GCs endocytose soluble substances from the lumen and transmit antigens to the underlying antigen-presenting cells (APCs). A variety of immuno-regulatory factors can promote the differentiation, maturation of GCs, and the secretion of mucin. The mucin secreted by GCs forms a mucus layer, which plays an important role in resisting the invasion of foreign bacteria and intestinal inherent microorganisms, regulating the immune performance of the body. Therefore, the present study mainly reviews the barrier function of the mucus layer, the mucus secreted by goblet cells, the protective effect against pathogenic bacteria, the delivery of luminal substances through GAPs and the relationship between GCs and the immune response.

Mucin-Derived O-Glycans Act as Endogenous Fiber and Sustain Mucosal Immune Homeostasis via Short-Chain Fatty Acid Production in Rat Cecum

Intestinal mucins escape digestion and enter the large bowel where they are degraded by the microbiota. To what extent and how mucins impact large-bowel physiology remain unclear. This study examined the large-bowel fermentation characteristics of mucins and mucin-derived O-glycan sugars and whether they affect gut immunity. Mucin secretion from the terminal ileum was determined from feces of ileorectostomized male Wistar rats (age 6 wk) fed an AIN76-based control diet (CD) for 15 d (experiment 1). Normal male Wistar rats (age 6 wk; 4 wk for experiment 4) were fed CD±porcine stomach mucin (PM) at 6 or 12g/kg diet, equivalent to 1.5 and 3 times the daily mucin secretion, for 14 d (experiment 2); CD±N-acetylglucosamine (GlcNAc), fucose, or N-acetylneuraminic acid at 10g/kg diet for 14 d (experiment 3); or CD±PM (15g/kg diet) or GlcNAc (10g/kg diet) for 29 d (experiment 4). SCFAs, microbial composition, and cecal O-glycan content were assessed. IgA+ plasma cells and regulatory T cells and inflammatory cytokine expression in the cecum were evaluated (experiment 4). Daily mucin secretion corresponded to 43.2 μmol of O-glycans. Cecal O-glycan contents were comparable between CD- and PM-fed rats. PM-fed rats harbored more mucin-degrading bacteria. Cecal concentrations of acetate (+37%) and n-butyrate (+73%) were higher in 12-g/kg PM diet-fed rats versus CD (P<0.05). Among O-glycan sugars, only GlcNAc produced higher n-butyrate concentrations (+68%) versus CD (P<0.05), with increased numbers of butyrate-producing bacteria. GlcNAc increased the abundance of IgA+ plasma cells (+29%) and regulatory T cells (+33%) versus CD, whereas PM increased IgA+ plasma cells (+25%) (all P<0.05). GlcNAc and PM decreased expression of Tnfa (-30%, -40%) and Ifng (-30%, -70%) versus CD (all P<0.05). Mucin-derived O-glycans act as endogenous fiber and maintain mucosal immune homeostasis via large-bowel SCFA production in rats.

Low temperature affects airway mucin secretion and promotes acute exacerbation of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) has a high incidence, and leads to irreversible lung dysfunction. Preventing COPD acute exacerbation (AECOPD) and delaying the progression of the disease are the focus of treatment. However, there is still a lack of precise and effective preventive measures. A significant feature of AECOPD is the high incidence in winter. The traditional concept is that cold air in winter can be accompanied by increased virus replication, environmental pollution, and reduced air humidity. Various confounding factors intertwine to promote the occurrence of AECOPD, and the impact of low temperature itself has been neglected. In recent years, with the development of molecular biology, more and more studies have found that abnormal secretion of airway mucin can lead to obstruction of mucus clearance, increase the chance of infection, and participate in the development of COPD. Low temperature can affect mucin secretion through various mechanisms. This article summarizes the particularity of COPD airway temperature and the related ways of low temperature leading to mucin changes. It draws people's attention to low temperature in order to carry out basic research and provide new intervention methods for predicting and preventing the occurrence of AECOPD.

Reconstruction of necrotic submandibular salivary gland using mesenchymal stem cells

BackgroundThe efficacy of mesnchymal stem cells (MSCs) to treat the necrotic tissue of salivary glands (SGs) has yet investigated. ObjectiveThis study was conducted to investigate the potential capacity of MSCs to restore the function and regenerate the necrotic submandiular gland in the rat animal model. MethodsTwenty-one Sprague–Dawley rats were provided from a breeding colony and randomly divided into three groups including the positive control or induced SG atrophy without treatment, the treatment group or induced SG atrophy with MSCs isolated transplantation and the negative control group consists of healthy rats. The atrophic and necrotic submandiular gland was induced using intraoral duct ligation of the main duct of submandiular gland for one month. The isolated stem cells were confirmed using flow cytometry for CD90 and CD 105. The isolated MSCs were cultured and injected to submandiular gland and the potential efficacy of MSCs to treat the atrophic submandibular glands was evaluated using histopathology on two weeks post-transplantation. To detect the acinar cell protein secretory granules, Alcian Blue and periodic acid shift (PAS) staining were done. For the demonstration of mitotic index or proliferation rate of the SG epithelia tissue, Ki-67 and Smbg proteins expression were evaluated using immunohistochemistry. ResultsThe locally injected MSCs could regenerate the overall histological structure of the necrotic submandibular gland tissue within 2 weeks of post-transplantation. Alcian Blue and PAS staining indicated that the mean amount of serous and mucin secretions in the treatment group was significantly increased compared to the positive control groups. We have also found that the treatment group significantly express higher Ki-67 protein, as a diagnostic marker for cell mitosis and proliferation rate, and lower Smbg protein, as a diagnostic marker, for damage to the submandibular gland than that of control group. ConclusionThis study demonstrates the therapeutic benefits of MSCs isolated from the SG in treating atrophic and necrotic SGs in a rat model. MSCs may be potential candidates for cell-based therapies targeting hypofunction of SG induced by a range of diseases or because of surgery and radiotherapy of head and neck cancers.

Exopolysaccharides from Bacillus amyloliquefaciens DMBA-K4 ameliorate dextran sodium sulfate-induced colitis via gut microbiota modulation

Accumulating evidences have reported that polysaccharide could alleviate colitis through the maintenance of intestinal homeostasis. In this study, an exopolysaccharide (EPS-K4) from Bacillus amyloliquefaciens was obtained via anionic-exchange chromatography which was with an average molecular weight of 10,067 Da and consisted of mannose, rhamnose, glucuronic acid, and glucose with a molar ratio of 40.09:23.65:11.42:17.68. Furthermore, administration of EPS-K4 relieved symptoms in colitis mice via gut microbiota modulation. The levels of pathogenic bacteria, such as Enterococcus and Escherichia-Shigella, were significantly suppressed. In contrast, the levels of Lactobacillus and intestinal microbiota diversity were increased. EPS-K4 could stimulate mucin secretion to maintain the integrity of the gut barrier and decrease the levels of virulent substances (endotoxin, diamine oxidase, and D-lactic acid) in serum. The pro-inflammatory cytokines (TNF-α) in serum were reduced, conversely, anti-inflammatory cytokines (IL-10) were increased. These findings indicated the possibility of EPS-K4 as a chemotherapy candidate for the prevention of colitis.

A mixed-type intraductal papillary mucinous neoplasm of the pancreas with a histologic combination of gastric and pancreatobiliary subtypes in a 70-year-old woman: a case report

BackgroundIntraductal papillary mucinous neoplasms are rare papillary pancreatic neoplasms arising from major pancreatic ducts, characterized by duct dilation and mucin secretion. They comprise approximately 1% of all exocrine neoplasms and are classified according to their anatomical sites into main duct-type, branch duct-type, and mixed-type intraductal papillary mucinous neoplasms. Histological examination plays a crucial role in distinguishing and classifying intraductal papillary mucinous neoplasms into gastric, intestinal, pancreatobiliary, and oncocytic subtypes.Case presentationWe present the case of a 70-year-old Syrian woman who was admitted to our hospital due to an intermittent epigastric pain accompanied by diarrhea and weight loss with a recent diagnosis of diabetes mellitus. Following clinical, laboratory, and radiological examination, distal pancreatectomy involving the body and the tail of the pancreas was performed. Interestingly, histological examination of the resected specimens revealed the diagnosis of a mixed-type intraductal papillary mucinous neoplasm with a unique combination of gastric and pancreatobiliary subtypes.ConclusionTo the best of our knowledge, the combination of multiple histological subtypes of intraductal papillary mucinous neoplasms has been recorded in a few studies with reference to the challenging histological detection. Herein, we report a rare case with a significant histological combination, highlighting the difficulties in differential diagnosis due to the absence of ancillary techniques, with a brief review on diagnostic methods, histological characteristics and surgical recommendations.

Mucins in Intestinal Mucosal Defense and Inflammation: Learning From Clinical and Experimental Studies

Throughout the gastrointestinal (GI) tract, a distinct mucus layer composed of highly glycosylated proteins called mucins plays an essential role in providing lubrication for the passage of food, participating in cell signaling pathways and protecting the host epithelium from commensal microorganisms and invading pathogens, as well as toxins and other environmental irritants. These mucins can be broadly classified into either secreted gel-forming mucins, those that provide the structural backbone for the mucus barrier, or transmembrane mucins, those that form the glycocalyx layer covering the underlying epithelial cells. Goblet cells dispersed among the intestinal epithelial cells are chiefly responsible for the synthesis and secretion of mucins within the gut and are heavily influenced by interactions with the immune system. Evidence from both clinical and animal studies have indicated that several GI conditions, including inflammatory bowel disease (IBD), colorectal cancer, and numerous enteric infections are accompanied by considerable changes in mucin quality and quantity. These changes include, but are not limited to, impaired goblet cell function, synthesis dysregulation, and altered post-translational modifications. The current review aims to highlight the structural and functional features as well as the production and immunological regulation of mucins and the impact these key elements have within the context of barrier function and host defense in intestinal inflammation.

Enhanced alcoholic liver disease in mice with intestine-specific farnesoid X receptor deficiency

AbstractAlcoholic fatty liver disease (AFLD) is one of the major causes of liver morbidity and mortality worldwide. We have previously shown that whole-body, but not hepatocyte-specific, deficiency of farnesoid X receptor (FXR) in mice worsens AFLD, suggesting that extrahepatic FXR deficiency is critical for AFLD development. Intestinal FXR is critical in suppressing hepatic bile acid (BA) synthesis by inducing fibroblast growth factor 15 (FGF15) in mice and FGF19 in humans. We hypothesized that intestinal FXR is critical for reducing AFLD development in mice. To test this hypothesis, we compared the AFLD severity in wild type (WT) and intestine-specific Fxr knockout (FXRInt−/−) mice following treatment with control or ethanol-containing diet. We found that FXRInt−/− mice were more susceptible to ethanol-induced liver steatosis and inflammation, compared with WT mice. Ethanol treatment altered the expression of hepatic genes involved in lipid and BA homeostasis, and ethanol detoxification. Gut FXR deficiency increased intestinal permeability, likely due to reduced mucosal integrity, as revealed by decreased secretion of Mucin 2 protein and lower levels of E-cadherin protein. In summary, intestinal FXR may protect AFLD development by maintaining gut integrity.Intestinal farnesoid X receptor (FXR) deficiency in mice leads to more severe liver injury and inflammation with ethanol treatment, which is associated with increased intestinal leakage. These results suggest that intestinal FXR may be critical in maintaining gut integrity and the epithelial barrier to protect the liver from ethanol-induced injury.

Hairy Region Concentrate of Pectin Strongly Stimulates Mucin Secretion in HT29-MTX Cells, but to a Lessor Degree in Rat Small Intestine

Pectin enhances mucin secretion in the rat small intestine. However, what structural features of pectin to stimulate mucin secretion remain unclear. The study aimed to clarify active constituents of pectin using a human goblet cell line, HT29-MTX. Various pectins at 100 mg/L commonly stimulated MUC5AC secretion, irrespective of their differences in molecular size, plant origin and degree of methoxylation, whereas other dietary fiber materials at 100 mg/L did not show any effects, except fucoidan. Hairy region concentrate (HRC) and its further fractions (F1-F3) were prepared by polygalacturonase treatment of citrus pectin and successive anion exchange chromatography. Neutral sugars, such as galactose and arabinose were enriched in these fractions. HRC and F1-F3 at 30 mg/L significantly increased MUC5AC secretion, which were 3 times more potent compared with a starting material (citrus pectin). Further, a dose-dependent study showed that F1 significantly increased MUC5AC secretion from at 0.3 mg/L, much stronger than that of mucin-secretagogue lipopolysaccharides. Rats consumed 5% apple pectin diet showed significant increases of luminal mucin contents and Muc2 expression in the small intestine, while the luminal mucin contents in rats consumed 1.5% HRC diet were increased by 24% compared to those in rats consumed control diet, but the difference did not reach significant. Thus, HRC is supposed to be active constituents of mucin-secretory effect of pectin in vitro. At present, however, the effect of HRC has not been verified in vivo.

Puerarin Rebuilding the Mucus Layer and Regulating Mucin-Utilizing Bacteria to Relieve Ulcerative Colitis.

The colonic mucus barrier serves as a primary defense against enteric pathogens; destruction of this mucus layer has been observed in ulcerative colitis patients. This study aims to investigate the possibility of rebuilding the colon mucus layer through puerarin supplementation, which can stimulate mucin secretion and goblet cells differentiation. After puerarin supplementation, the thickness of colon mucus layer was increased and the permeability was reduced. The erosion of intestinal epithelium by bacteria was blocked, and the loss of epithelial integrity was alleviated. Puerarin also altered the composition of mucin-utilizing bacteria, which influenced the mucus permeability. Levels of short-chain fatty acids (SCFAs) were increased after puerarin supplementation, which as a direct source of energy for the proliferation of epithelia and goblet cells. This study demonstrated that enhancement of mucin secretion to relieve ulcerative colitis (UC) by puerarin supplementation is feasible, and the regulation of mucin-utilizing bacteria and the increased levels of SCFAs may be the main reasons.

Zinc Deficiency Disturbs Mucin Expression, O-Glycosylation and Secretion by Intestinal Goblet Cells.

Approximately 1 billion people worldwide suffer from zinc deficiency, with severe consequences for their well-being, such as critically impaired intestinal health. In addition to an extreme degeneration of the intestinal epithelium, the intestinal mucus is seriously disturbed in zinc-deficient (ZD) animals. The underlying cellular processes as well as the relevance of zinc for the mucin-producing goblet cells, however, remain unknown. To this end, this study examines the impact of zinc deficiency on the synthesis, production, and secretion of intestinal mucins as well as on the zinc homeostasis of goblet cells using the in vitro goblet cell model HT-29-MTX. Zinc deprivation reduced their cellular zinc content, changed expression of the intestinal zinc transporters ZIP-4, ZIP-5, and ZnT1 and increased their zinc absorption ability, outlining the regulatory mechanisms of zinc homeostasis in goblet cells. Synthesis and secretion of mucins were severely disturbed during zinc deficiency, affecting both MUC2 and MUC5AC mRNA expression with ongoing cell differentiation. A lack of zinc perturbed mucin synthesis predominantly on the post-translational level, as ZD cells produced shorter O-glycans and the main O-glycan pattern was shifted in favor of core-3-based mucins. The expression of glycosyltransferases that determine the formation of core 1-4 O-glycans was altered in zinc deficiency. In particular, B3GNT6 mRNA catalyzing core 3 formation was elevated and C2GNT1 and C2GNT3 elongating core 1 were downregulated in ZD cells. These novel insights into the molecular mechanisms impairing intestinal mucus stability during zinc deficiency demonstrate the essentiality of zinc for the formation and maintenance of this physical barrier.