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ACS Synthetic Biology Feb 2020Mucus in the gastrointestinal (GI) tract is the primary point-of-interaction between humans and their gut microbiota. This intimates that mucus not only ensures...
Mucus in the gastrointestinal (GI) tract is the primary point-of-interaction between humans and their gut microbiota. This intimates that mucus not only ensures protection against endogenous and exogenous opportunists but also provisions for the human microbiota to reside and flourish. With the emergence of living therapeutics, engineered microbes can deliver and produce increasingly complex medicine, and controlling the mucoadhesive properties of different microbial chassis can dictate dose-response in a patient. Here we present a redesigned, , plate-based assay to measure the mucus adhesion of various probiotics. Cell-mucus interactions were isolated by immobilizing mucus to the plate surface. Binding parameters were derived for each probiotic strain by measuring cell adhesion over a wide range of cell concentrations, providing dose-dependent adhesion metrics. Surface proteins and cell components known to influence mucoadhesion were then heterologously expressed or altered in MG1363 and Nissle 1917 to control mucus-binding capacity, avidity, and cooperativity.
Topics: Animals; Bacterial Adhesion; Escherichia coli; Fluoresceins; Humans; Lactococcus lactis; Microscopy, Fluorescence; Mucin-2; Mucus; Probiotics; Swine
PubMed: 31909976
DOI: 10.1021/acssynbio.9b00356 -
Annual Review of Cell and Developmental... Oct 2018We review what is currently understood about how the structure of the primary solid component of mucus, the glycoprotein mucin, gives rise to the mechanical and... (Review)
Review
We review what is currently understood about how the structure of the primary solid component of mucus, the glycoprotein mucin, gives rise to the mechanical and biochemical properties of mucus that are required for it to perform its diverse physiological roles. Macroscale processes such as lubrication require mucus of a certain stiffness and spinnability, which are set by structural features of the mucin network, including the identity and density of cross-links and the degree of glycosylation. At the microscale, these same features affect the mechanical environment experienced by small particles and play a crucial role in establishing an interaction-based filter. Finally, mucin glycans are critical for regulating microbial interactions, serving as receptor binding sites for adhesion, as nutrient sources, and as environmental signals. We conclude by discussing how these structural principles can be used in the design of synthetic mucin-mimetic materials and provide suggestions for directions of future work in this field.
Topics: Animals; Glycoproteins; Glycosylation; Humans; Mucin-1; Mucus; Permeability; Rheology; Structure-Activity Relationship
PubMed: 30296390
DOI: 10.1146/annurev-cellbio-100617-062818 -
European Journal of Pharmaceutics and... Apr 2022Gastrointestinal (GI) mucus is continuously secreted and lines the entire length of the GI tract. Essential for health, it keeps the noxious luminal content away from...
Gastrointestinal (GI) mucus is continuously secreted and lines the entire length of the GI tract. Essential for health, it keeps the noxious luminal content away from the epithelium. Our aim was to characterize the composition and structure of mucus throughout the various GI segments in dog. Mucus was collected from the stomach, small intestine (duodenum, jejunum, ileum), and large intestine (cecum, proximal and distal colon) from dogs. Composition was determined by multi-omics. Structural properties were investigated using cryoSEM and rheology. GI mucus contained 74-95% water and maintained a pH around 6.5. The proteome was similar across the different GI segments. The highest abundant secreted gel-forming mucin in the gastric mucus was mucin 5AC, whether mucin 2 had highest abundance in the intestinal mucus. Lipid and metabolite abundance was generally higher in the jejunal mucus than the colonic mucus. CryoSEM microscopy revealed smaller pore size in small intestinal mucus, which increased in the large intestine. All mucus samples showed shear-thinning behavior and characteristics of gel-like structure. In conclusion, the mucus is a highly viscous and hydrated material. These data provide an important baseline for future studies on human and canine intestinal diseases and the dog model in drug absorption.
Topics: Animals; Colon; Dogs; Gastrointestinal Tract; Intestinal Mucosa; Intestine, Small; Mucus; Stomach
PubMed: 35227857
DOI: 10.1016/j.ejpb.2022.02.019 -
Chest Nov 2016Although mucus is a normal product of the tracheobronchial tree, some diseases of the respiratory tract are characterized by unusually thick (inspissated) forms of mucus... (Review)
Review
Although mucus is a normal product of the tracheobronchial tree, some diseases of the respiratory tract are characterized by unusually thick (inspissated) forms of mucus that accumulate within the airways. These are known as mucus plugs. The pathologic composition of these plugs is surprisingly diverse and, in many cases, correlates with distinctive clinical, radiologic, and bronchoscopic findings. The best-known conditions that involve mucus plugs are allergic bronchopulmonary aspergillosis, plastic bronchitis, and asthma. Other lung diseases occasionally associated with plugs within the airways include Aspergillus tracheobronchitis, hyper-IgE syndrome, exogenous lipoid pneumonia, pulmonary alveolar proteinosis, and chronic eosinophilic pneumonia. In this review, we describe and illustrate the bronchoscopic, pathologic, and imaging findings in respiratory disorders characterized by mucus plugs or plugs composed of other similar materials. Recognition of the characteristic appearance and differential diagnosis of mucus plugs will hopefully facilitate diagnosis and management of these diseases.
Topics: Airway Obstruction; Bronchi; Bronchoscopy; Humans; Mucus
PubMed: 27445091
DOI: 10.1016/j.chest.2016.07.003 -
European Journal of Pharmaceutics and... Oct 2015The present review provides an overview of methods and techniques for studying interactions of micro- and nanoparticulate drug delivery system with mucus. Nanocarriers... (Review)
Review
The present review provides an overview of methods and techniques for studying interactions of micro- and nanoparticulate drug delivery system with mucus. Nanocarriers trapped by mucus are featuring a change in particle size and zeta potential that can be utilized to predict their mucus permeation behavior. Furthermore, interactions between nanoparticulate drug delivery systems and mucus layer modify the viscoelasticity of mucus which can be detected via rheological studies and quartz crystal microbalance with dissipation monitoring (QCM-D) analysis. Having a closer look at molecular interactions between drug carrier and mucus small-angle neutron scattering (SANS) is an appropriate analysis technique. Moreover, different methods to determine particle diffusion in mucus such as the newly established Transwell diffusion system, rotating silicone tube technique, multiple-particle tracking (MPT) and diffusion NMR are summarized within this review. The explanations and discussed pros and cons of collated methods and techniques should provide a good starting point for all those looking forward to move in this interesting field.
Topics: Absorption, Physicochemical; Animals; Diffusion; Drug Carriers; Drug Delivery Systems; Humans; Microspheres; Mucous Membrane; Mucus; Nanoparticles; Particle Size; Permeability; Pharmacokinetics; Surface Properties; Viscosity
PubMed: 25641005
DOI: 10.1016/j.ejpb.2015.01.005 -
Cell and Tissue Research Mar 2017Airway mucus obstruction is a hallmark of many chronic lung diseases including rare genetic disorders such as cystic fibrosis (CF) and primary ciliary dyskinesia, as... (Review)
Review
Airway mucus obstruction is a hallmark of many chronic lung diseases including rare genetic disorders such as cystic fibrosis (CF) and primary ciliary dyskinesia, as well as common lung diseases such as asthma and chronic obstructive pulmonary disease (COPD), which have emerged as a leading cause of morbidity and mortality worldwide. However, the role of excess airway mucus in the in vivo pathogenesis of these diseases remains poorly understood. The generation of mice with airway-specific overexpression of epithelial Na channels (ENaC), exhibiting airway surface dehydration (mucus hyperconcentration), impaired mucociliary clearance (MCC) and mucus plugging, led to a model of muco-obstructive lung disease that shares key features of CF and COPD. In this review, we summarize recent progress in the understanding of causes of impaired MCC and in vivo consequences of airway mucus obstruction that can be inferred from studies in βENaC-overexpressing mice. These studies confirm that mucus hyperconcentration on airway surfaces plays a critical role in the pathophysiology of impaired MCC, mucus adhesion and airway plugging that cause airflow obstruction and provide a nidus for bacterial infection. In addition, these studies support the emerging concept that excess airway mucus per se, probably via several mechanisms including hypoxic epithelial necrosis, retention of inhaled irritants or allergens, and potential immunomodulatory effects, is a potent trigger of chronic airway inflammation and associated lung damage, even in the absence of bacterial infection. Finally, these studies suggest that improvement of mucus clearance may be a promising therapeutic strategy for a spectrum of muco-obstructive lung diseases.
Topics: Airway Remodeling; Animals; Chronic Disease; Humans; Inflammation; Lung; Lung Diseases; Mucus
PubMed: 28108847
DOI: 10.1007/s00441-016-2562-z -
Respiratory Care Jun 2015Airway mucus hypersecretion and secretion retention can result from inflammation, irritation, stimulation, or mucus-producing tumors. Secretion clearance can be... (Review)
Review
Airway mucus hypersecretion and secretion retention can result from inflammation, irritation, stimulation, or mucus-producing tumors. Secretion clearance can be furthered hampered by ciliary dysfunction and by weakness or restrictive lung disease, leading to an ineffective cough. There are a number of different mucoactive medications that have been used to reduce hypersecretion, make secretions easier to transport, or increase the efficiency of cough or mucus clearance. In this paper, I review the pathophysiology of secretory hyper-responsiveness and mucus hypersecretion and discuss the different aerosol medications that can be used to augment secretion clearance.
Topics: Administration, Inhalation; Aerosols; Cough; Expectorants; Humans; Lung Diseases; Mucociliary Clearance; Mucus
PubMed: 26070577
DOI: 10.4187/respcare.04087 -
Advanced Drug Delivery Reviews Jan 2018The mucosa of the gastrointestinal tract, eyes, nose, lungs, cervix and vagina is lined by epithelium interspersed with mucus-secreting goblet cells, all of which... (Review)
Review
The mucosa of the gastrointestinal tract, eyes, nose, lungs, cervix and vagina is lined by epithelium interspersed with mucus-secreting goblet cells, all of which contribute to their unique functions. This mucus provides an integral defence to the epithelium against noxious agents and pathogens. However, it can equally act as a barrier to drugs and delivery systems targeting epithelial passive and active transport mechanisms. This review highlights the various mucins expressed at different mucosal surfaces on the human body, and their role in creating a mucoid architecture to protect epithelia with specialized functions. Various factors compromising the barrier properties of mucus have been discussed, with an emphasis on how disease states and microbiota can alter the physical properties of mucus. For instance, Akkermansia muciniphila, a bacterium found in higher levels in the gut of lean individuals induces the production of a thickened gut mucus layer. The aims of this article are to elucidate the different physiological, biochemical and physical properties of bodily mucus, a keen appreciation of which will help circumvent the slippery slope of challenges faced in achieving effective mucosal drug and gene delivery.
Topics: Animals; Drug Delivery Systems; Humans; Mucus
PubMed: 29108861
DOI: 10.1016/j.addr.2017.10.014 -
Molecular Therapy : the Journal of the... Dec 2016Recent evidence suggests that the airway mucus gel layer may be impermeable to the viral and synthetic gene vectors used in past inhaled gene therapy clinical trials for... (Review)
Review
Recent evidence suggests that the airway mucus gel layer may be impermeable to the viral and synthetic gene vectors used in past inhaled gene therapy clinical trials for diseases like cystic fibrosis. These findings support the logic that inhaled gene vectors that are incapable of penetrating the mucus barrier are unlikely to provide meaningful benefit to patients. In this review, we discuss the biochemical and biophysical features of mucus that contribute its barrier function, and how these barrier properties may be reinforced in patients with lung disease. We next review biophysical techniques used to assess the potential ability of gene vectors to penetrate airway mucus. Finally, we provide new data suggesting that fresh human airway mucus should be used to test the penetration rates of gene vectors. The physiological barrier properties of spontaneously expectorated CF sputum remained intact up to 24 hours after collection when refrigerated at 4 °C. Conversely, the barrier properties were significantly altered after freezing and thawing of sputum samples. Gene vectors capable of overcoming the airway mucus barrier hold promise as a means to provide the widespread gene transfer throughout the airway epithelium required to achieve meaningful patient outcomes in inhaled gene therapy clinical trials.
Topics: Biological Transport; Genetic Therapy; Genetic Vectors; Humans; Lung Diseases; Mucus; Sputum
PubMed: 27646604
DOI: 10.1038/mt.2016.182 -
Chemical Society Reviews Jul 2020Mucosal tissues constitute the largest interface between the body and the surrounding environment and they regulate the access of molecules, supramolecular structures,... (Review)
Review
Mucosal tissues constitute the largest interface between the body and the surrounding environment and they regulate the access of molecules, supramolecular structures, particulate matter, and pathogens into it. All mucosae are characterized by an outer mucus layer that protects the underlying cells from physicochemical, biological and mechanical insults, a mono-layered or stratified epithelium that forms tight junctions and controls the selective transport of solutes across it and associated lymphoid tissues that play a sentinel role. Mucus is a gel-like material comprised mainly of the glycoprotein mucin and water and it displays both hydrophilic and hydrophobic domains, a net negative charge, and high porosity and pore interconnectivity, providing an efficient barrier for the absorption of therapeutic agents. To prolong the residence time, absorption and bioavailability of a broad spectrum of active compounds upon mucosal administration, mucus-penetrating and mucoadhesive particles have been designed by tuning the chemical composition, the size, the density, and the surface properties. The benefits of utilizing nanomaterials that interact intimately with mucosae by different mechanisms in the nanomedicine field have been extensively reported. To ensure the safety of these nanosystems, their compatibility is evaluated in vitro and in vivo in preclinical and clinical trials. Conversely, there is a growing concern about the toxicity of nanomaterials dispersed in air and water effluents that unintentionally come into contact with the airways and the gastrointestinal tract. Thus, deep understanding of the key nanomaterial properties that govern the interplay with mucus and tissues is crucial for the rational design of more efficient drug delivery nanosystems (nanomedicine) and to anticipate the fate and side-effects of nanoparticulate matter upon acute or chronic exposure (nanotoxicology). This review initially overviews the complex structural features of mucosal tissues, including the structure of mucus, the epithelial barrier, the mucosal-associated lymphatic tissues and microbiota. Then, the most relevant investigations attempting to identify and validate the key particle features that govern nanomaterial-mucosa interactions and that are relevant in both nanomedicine and nanotoxicology are discussed in a holistic manner. Finally, the most popular experimental techniques and the incipient use of mathematical and computational models to characterize these interactions are described.
Topics: Animals; Humans; Mucus; Nanomedicine; Nanostructures
PubMed: 32538405
DOI: 10.1039/c8cs00948a