A slippery slope: On the origin, role and physiology of mucus

Abstract

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.

Introduction

The mucosal barriers of the human body are integral not only to protect against immunological, chemical and mechanical stresses, but have also increasingly gained prominence for their key role in drug delivery. Mucosa consists of one or more layers of epithelial cells overlying a layer of loose connective tissue, the lamina propria; which is a key part of the mucosal immune system, and followed by the submucosa, consisting of submucosal glands and muscular layers. Some specialized mucosal epithelial cells (such as goblet cells) secrete mucus glycoproteins, which form a layer of viscoelastic mucus on the surface of epithelia. Mucus per se is a semi-permeable network that enables the exchange of nutrients, water, gases, hormones and gametes, whilst being impermeable to most bacteria and pathogens due to its steric obstruction and adhesion properties [1], [2]. Cell surface mucins are a prominent feature of the apical glycocalyx of all mucosal epithelia [3].

The properties and functions of mucus secretions are adapted to suit the anatomical location, and can change (as cause or consequence) in disease states where mucus hypersecretion or altered mucin expression is observed [3], [4]. Indeed, the differing compositions of the mucosa and mucus of the eye, nose, lower respiratory tract, gastrointestinal tract, cervix and vagina are all individually unique and adapted to perform the functions of these barriers seamlessly, whilst simultaneously protecting the underlying epithelium. For instance, the epithelia of the respiratory tract form a mucociliary escalator [4] that aids the movement and expulsion of trapped inhaled foreign bodies, whereas the transmembrane mucins tethered in the periciliary layer (PCL) form a sieve restricting particles > 40 nm from translocating into the PCL, thereby maintaining sterility [5], [6]. In turn, a double-layer mucus architecture in the hostile zones of the stomach and colon protect the underlying lining from acid, enzymes (pepsin and proteases) and microbial aggressors [7], [8]. Endogenous hormone secretion from the epithelia of the cervix and vagina also changes the viscoelasticity of cervical mucus in different stages of the menstrual cycle, to either promote or prevent conception [9]. Dietary influences have also been observed to modulate the colonic mucus; low-fibre diets, for instance, have been shown to lead to thinning of mucus owing to associated bacterial colonization [10], [11]. This thinning exposes the epithelium to bacterial contact and translocation into the mucosa, eliciting an immunological response and further damage and inflammation, as seen in ulcerative colitis [12]. These properties of mucus in the healthy state, however, make it an excellent guard against immunological as well as chemical and mechanical damage, thereby allowing the mucosa to carry out its normal physiological functions.

While mucus precludes the permeation of drugs, proteins, peptides and nanoparticulate drug delivery systems [13], [14], certain capsid viruses have been observed to diffuse through cervicovaginal mucus at rates similar to that in water [15], implying that this barrier cannot restrict surface neutral particles from reaching and infecting the epithelium. Additionally, the mucus pore size and rheology also influence this phenomenon [16]. This property has been exploited towards the design of muco-inert polyethylene glycol coated nanoparticles that are muco-penetrating for cervico-vaginal and ocular delivery [17], [18]. Overall, this knowledge can be used to design drug delivery systems to diffuse ‘upstream’ against the secretion and shedding of mucus to deliver drugs to epithelia.

Furthermore, mucus secreting epithelia continuously secrete and turnover mucus to create a physiological clearance mechanism. However, this protective mechanism can also cause undesirable drug clearance, a common barrier to drug delivery. As such, in order to deliver the drug payload, and hence achieve the desired drug exposure, prolonged contact of the formulation at the target site is desirable. Mucoadhesive systems have been employed by virtue of their ability to interact with the mucin glycoprotein; whereby mucoadhesive excipients by swelling and interdiffusion of the polymer chains bond with mucin fibres through hydrogen bonding, disulfide bonding, electrostatic and/or hydrophobic interactions. An in-depth review of mucoadhesion as a concept to increase residence time is beyond the scope of this review which focuses on the physiological aspects of mucosa and mucus and therefore the following references [19], [20], [21], [22], [23] will provide the reader with greater insight in the area of mucoadhesion.

This article reviews the mucosal histology in relation to the arrangement of goblet cells and submucosal glands. The biosynthesis and release mechanism of mucin from the goblet cells and the physiological and mechanical characteristics of the mucus lining different epithelia are here discussed. Additionally, the functionality of the mucus lining and its dynamic composition are discussed in their role of health and disease.