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Physiological Reviews Oct 2022The mucus clearance system is the dominant mechanical host defense system of the human lung. Mucus is cleared from the lung by cilia and airflow, including both... (Review)
Review
The mucus clearance system is the dominant mechanical host defense system of the human lung. Mucus is cleared from the lung by cilia and airflow, including both two-phase gas-liquid pumping and cough-dependent mechanisms, and mucus transport rates are heavily dependent on mucus concentration. Importantly, mucus transport rates are accurately predicted by the gel-on-brush model of the mucociliary apparatus from the relative osmotic moduli of the mucus and periciliary-glycocalyceal (PCL-G) layers. The fluid available to hydrate mucus is generated by transepithelial fluid transport. Feedback interactions between mucus concentrations and cilia beating, via purinergic signaling, coordinate Na absorptive vs Cl secretory rates to maintain mucus hydration in health. In disease, mucus becomes hyperconcentrated (dehydrated). Multiple mechanisms derange the ion transport pathways that normally hydrate mucus in muco-obstructive lung diseases, e.g., cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis (NCFB), and primary ciliary dyskinesia (PCD). A key step in muco-obstructive disease pathogenesis is the osmotic compression of the mucus layer onto the airway surface with the formation of adherent mucus plaques and plugs, particularly in distal airways. Mucus plaques create locally hypoxic conditions and produce airflow obstruction, inflammation, infection, and, ultimately, airway wall damage. Therapies to clear adherent mucus with hydrating and mucolytic agents are rational, and strategies to develop these agents are reviewed.
Topics: Cystic Fibrosis; Humans; Lung; Mucociliary Clearance; Mucus; Pulmonary Disease, Chronic Obstructive
PubMed: 35001665
DOI: 10.1152/physrev.00004.2021 -
Cell Mar 2022Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier...
Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD.
Topics: Animals; Gastrointestinal Microbiome; Homeostasis; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Mice; Mucus; Sialyltransferases; Symbiosis
PubMed: 35303419
DOI: 10.1016/j.cell.2022.02.013 -
Annual Review of Biochemistry Jun 2020Generating the barriers that protect our inner surfaces from bacteria and other challenges requires large glycoproteins called mucins. These come in two types,... (Review)
Review
Generating the barriers that protect our inner surfaces from bacteria and other challenges requires large glycoproteins called mucins. These come in two types, gel-forming and transmembrane, all characterized by large, highly -glycosylated mucin domains that are diversely decorated by Golgi glycosyltransferases to become extended rodlike structures. The general functions of mucins on internal epithelial surfaces are to wash away microorganisms and, even more importantly, to build protective barriers. The latter function is most evident in the large intestine, where the inner mucus layer separates the numerous commensal bacteria from the epithelial cells. The host's conversion of MUC2 to the outer mucus layer allows bacteria to degrade the mucin glycans and recover the energy content that is then shared with the host. The molecular nature of the mucins is complex, and how they construct the extracellular complex glycocalyx and mucus is poorly understood and a future biochemical challenge.
Topics: Animals; Carbohydrate Conformation; Carbohydrate Sequence; Gastrointestinal Microbiome; Gene Expression; Glycocalyx; Glycosylation; Glycosyltransferases; Goblet Cells; Humans; Mucins; Mucus; Symbiosis
PubMed: 32243763
DOI: 10.1146/annurev-biochem-011520-105053 -
Gut Dec 2020The gastrointestinal tract is often considered as a key organ involved in the digestion of food and providing nutrients to the body for proper maintenance. However, this... (Review)
Review
The gastrointestinal tract is often considered as a key organ involved in the digestion of food and providing nutrients to the body for proper maintenance. However, this system is composed of organs that are extremely complex. Among the different parts, the intestine is viewed as an incredible surface of contact with the environment and is colonised by hundreds of trillions of gut microbes. The role of the gut barrier has been studied for decades, but the exact mechanisms involved in the protection of the gut barrier are various and complementary. Among them, the integrity of the mucus barrier is one of the first lines of protection of the gastrointestinal tract. In the past, this 'slimy' partner was mostly considered a simple lubricant for facilitating the progression of the food bolus and the stools in the gut. Since then, different researchers have made important progress, and currently, the regulation of this mucus barrier is gaining increasing attention from the scientific community. Among the factors influencing the mucus barrier, the microbiome plays a major role in driving mucus changes. Additionally, our dietary habits (ie, high-fat diet, low-fibre/high-fibre diet, food additives, pre- probiotics) influence the mucus at different levels. Given that the mucus layer has been linked with the appearance of diseases, proper knowledge is highly warranted. Here, we debate different aspects of the mucus layer by focusing on its chemical composition, regulation of synthesis and degradation by the microbiota as well as some characteristics of the mucus layer in both physiological and pathological situations.
Topics: Diet; Gastrointestinal Microbiome; Gastrointestinal Tract; Host Microbial Interactions; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Microbiota; Mucins; Mucus; Probiotics
PubMed: 32917747
DOI: 10.1136/gutjnl-2020-322260 -
Respiratory Care Feb 2020Although better insights into the natural course of cystic fibrosis (CF) have led to treatment approaches that have improved pulmonary health and increased the life... (Review)
Review
Although better insights into the natural course of cystic fibrosis (CF) have led to treatment approaches that have improved pulmonary health and increased the life expectancy of individuals with this disorder, lung disease remains the main cause of morbidity and mortality in patients with CF. Evidence suggests that airway epithelial defects in ions-water transport lead to dehydrated mucus, impaired mucus clearance, and mucus adhesion to airway surfaces. An increase in mucin secretion is also suggested by the formation of endobronchial mucus plaques and plugs, which become the main sites of air flow obstruction, infection, and inflammation conducing to early small airways disease followed by the development of bronchiectasis. The lung involvement is usually progressive with intermittent exacerbations. Aggressive management and advances in treatment delay, but, do not prevent progression of lung disease. Respiratory failure ensues and is the major cause of death. The lung parenchyma is virtually untouched for much of the course of the disease. This review focuses on the lung involvement in cystic fibrosis and summarizes new developments on the diagnostic approach of CF and pathogenesis of related lung disease. Current therapeutic modalities, novel therapies targeting the basic genetic defect, and lung transplantation are also reviewed.
Topics: Bronchiectasis; Cystic Fibrosis; Humans; Lung; Mucociliary Clearance; Mucus
PubMed: 31772069
DOI: 10.4187/respcare.06697 -
Cell Oct 2022Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier...
Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8CGRP nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demonstrate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection.
Topics: Mice; Humans; Animals; Goblet Cells; Nociceptors; Calcitonin Gene-Related Peptide; Colitis; Mucus; Receptor Activity-Modifying Protein 1
PubMed: 36243004
DOI: 10.1016/j.cell.2022.09.024 -
Cell Host & Microbe Mar 2023Colonic goblet cells are specialized epithelial cells that secrete mucus to physically separate the host and its microbiota, thus preventing bacterial invasion and...
Colonic goblet cells are specialized epithelial cells that secrete mucus to physically separate the host and its microbiota, thus preventing bacterial invasion and inflammation. How goblet cells control the amount of mucus they secrete is unclear. We found that constitutive activation of autophagy in mice via Beclin 1 enables the production of a thicker and less penetrable mucus layer by reducing endoplasmic reticulum (ER) stress. Accordingly, genetically inhibiting Beclin 1-induced autophagy impairs mucus secretion, while pharmacologically alleviating ER stress results in excessive mucus production. This ER-stress-mediated regulation of mucus secretion is microbiota dependent and requires the Crohn's-disease-risk gene Nod2. Overproduction of mucus alters the gut microbiome, specifically expanding mucus-utilizing bacteria, such as Akkermansia muciniphila, and protects against chemical and microbial-driven intestinal inflammation. Thus, ER stress is a cell-intrinsic switch that limits mucus secretion, whereas autophagy maintains intestinal homeostasis by relieving ER stress.
Topics: Animals; Mice; Goblet Cells; Beclin-1; Inflammation; Mucus; Autophagy; Intestinal Mucosa
PubMed: 36738733
DOI: 10.1016/j.chom.2023.01.006 -
Cell Host & Microbe Jul 2023The colon mucus layer is organized with an inner colon mucus layer that is impenetrable to bacteria and an outer mucus layer that is expanded to allow microbiota... (Review)
Review
The colon mucus layer is organized with an inner colon mucus layer that is impenetrable to bacteria and an outer mucus layer that is expanded to allow microbiota colonization. A major component of mucus is MUC2, a glycoprotein that is extensively decorated, especially with O-glycans. In the intestine, goblet cells are specialized in controlling glycosylation and making mucus. Some microbiota members are known to encode multiple proteins that are predicted to bind and/or cleave mucin glycans. The interactions between commensal microbiota and host mucins drive intestinal colonization, while at the same time, the microbiota can utilize the glycans on mucins and affect the colonic mucus properties. This review will examine this interaction between commensal microbes and intestinal mucins and discuss how this interplay affects health and disease.
Topics: Intestinal Mucosa; Mucin-2; Intestines; Mucus; Mucins; Microbiota; Polysaccharides
PubMed: 37442097
DOI: 10.1016/j.chom.2023.05.026 -
Advances in Nutrition (Bethesda, Md.) Jan 2020The intestinal tract is the largest barrier between a person and the environment. In this role, the intestinal tract is responsible not only for absorbing essential... (Review)
Review
The intestinal tract is the largest barrier between a person and the environment. In this role, the intestinal tract is responsible not only for absorbing essential dietary nutrients, but also for protecting the host from a variety of ingested toxins and microbes. The intestinal barrier system is composed of a mucus layer, intestinal epithelial cells (IECs), tight junctions (TJs), immune cells, and a gut microbiota, which are all susceptible to external factors such as dietary fats. When components of this barrier system are disrupted, intestinal permeability to luminal contents increases, which is implicated in intestinal pathologies such as inflammatory bowel disease, necrotizing enterocolitis, and celiac disease. Currently, there is mounting evidence that consumption of excess dietary fats can enhance intestinal permeability differentially. For example, dietary fat modulates the expression and distribution of TJs, stimulates a shift to barrier-disrupting hydrophobic bile acids, and even induces IEC oxidative stress and apoptosis. In addition, a high-fat diet (HFD) enhances intestinal permeability directly by stimulating proinflammatory signaling cascades and indirectly via increasing barrier-disrupting cytokines [TNFα, interleukin (IL) 1B, IL6, and interferon γ (IFNγ)] and decreasing barrier-forming cytokines (IL10, IL17, and IL22). Finally, an HFD negatively modulates the intestinal mucus composition and enriches the gut microflora with barrier-disrupting species. Although further research is necessary to understand the precise role HFDs play in intestinal permeability, current data suggest a stronger link between diet and intestinal disease than was first thought to exist. Therefore, this review seeks to highlight the various ways an HFD disrupts the gut barrier system and its many implications in human health.
Topics: Animals; Bile Acids and Salts; Cytokines; Diet, High-Fat; Dietary Fats; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Inflammation; Intestinal Mucosa; Mucus; Permeability; Tight Junctions
PubMed: 31268137
DOI: 10.1093/advances/nmz061 -
Frontiers in Cellular and Infection... 2023The female reproductive tract harbours hundreds of bacterial species and produces numerous metabolites. The uterine cervix is located between the upper and lower parts... (Review)
Review
The female reproductive tract harbours hundreds of bacterial species and produces numerous metabolites. The uterine cervix is located between the upper and lower parts of the female genital tract. It allows sperm and birth passage and hinders the upward movement of microorganisms into a relatively sterile uterus. It is also the predicted site for sexually transmitted infection (STI), such as Chlamydia, human papilloma virus (HPV), and human immunodeficiency virus (HIV). The healthy cervicovaginal microbiota maintains cervical epithelial barrier integrity and modulates the mucosal immune system. Perturbations of the microbiota composition accompany changes in microbial metabolites that induce local inflammation, damage the cervical epithelial and immune barrier, and increase susceptibility to STI infection and relative disease progression. This review examined the intimate interactions between the cervicovaginal microbiota, relative metabolites, and the cervical epithelial-, immune-, and mucus barrier, and the potent effect of the host-microbiota interaction on specific STI infection. An improved understanding of cervicovaginal microbiota regulation on cervical microenvironment homeostasis might promote advances in diagnostic and therapeutic approaches for various STI diseases.
Topics: Male; Female; Humans; Semen; Cervix Uteri; Sexually Transmitted Diseases; Microbiota; Mucus; Vagina
PubMed: 36909729
DOI: 10.3389/fcimb.2023.1124591