Why Mucus and Phlegm Matter in Health and Disease - American Society for Microbiology

It's mucus season—the time of year this sticky goo makes an appearance in the form of runny noses and phlegmy coughs. While most people are only aware of mucus when they are sick, their organs are blanketed with the stuff year-round. And, when it comes to the microbes living in our bodies, mucus is incredibly important. It provides a spatial and nutritional niche for diverse organisms to thrive, while also preventing them from getting too close to host tissues. Mucus also regulates microbial growth, metabolism and virulence, ultimately controlling the composition of microbial communities throughout the body. As such, scientists are looking at how to exploit mucus-microbe interactions to foster human health.

What is Mucus?

Mucins, the key components of mucus, are further embellished with glycan molecules.

Source: Wu C.M. et al./npj biofilms and microbiomes, 2023 under a CC BY 4.0 DEED license.

Mucus is found in creatures spanning the tree of life, from corals to people. In humans and other mammals, the slick goop coats epithelial tissues, including those in the mouth, lungs, gut and urogenital tract. In these regions, mucus protects cells from physical and enzymatic stress, heals wounds and selectively filters particles that can pass through to underlying tissues.

Structurally, mucus is made up of molecules (glycoproteins) called mucins that are released by secretory epithelial cells (e.g., goblet cells); it also contains water, lipids, DNA, antimicrobial compounds and more. There are 21 different mucin proteins encoded by the human body. Glycans (long sugar molecules) can be enzymatically tacked onto the mucin protein backbone, creating a "bottle brush" appearance characteristic of mucins. The addition of glycans creates an astounding array of diversity in mucin structure and function, which ranges from cell signaling to immune responses.

The dominant type of mucin and its glycosylation pattern, as well as its secretion rate and viscoelasticity, vary depending on body location and even within different areas in the same organ (e.g., along the gastrointestinal tract). These variations indicate that mucus is attuned to the environment and needs of a given body region—that is, the mucus coating an eyeball necessarily differs from the mucus that covers the gut. 

Mucus and Microbes

Regardless of body-site-specific differences in mucus production and composition, 1 thing holds true: where there is mucus, there are microbes. A primary function of mucus is to prevent organisms from directly interacting with and traversing host tissues, which can lead to inflammation and other negative outcomes. Mucus also regulates the composition and function of microbial communities in several ways.

Mucus Molds Microbial Organization

For one, mucus forms a scaffold in which microbial populations are housed and organized. Where microbes reside within mucus depends on their physiology, interactions with each other and the properties of mucus itself. For example, the colon (the most microbially loaded location in the body) is draped in 2 layers of mucus—the outermost layer contains the most gut bacteria, whereas, due to its high density and small pore sizes, the inner layer is generally devoid of microbes. The texture of mucus also matters. A recent study showed that it is easier for bacteria to move coherently in groups in thick rather than thin mucus, which likely influences the spatial organization of bacterial communities. Chemical features of mucus (e.g., glycans) further shape microbial spatial characteristics, including biofilm formation and distribution and bacterial adhesion and aggregation.

Bacteria reside in the mucus layer of the gut. Here, the distal colon of a mouse harboring either a single species of gut bacteria (A; Muribaculum intestinale) or 2 species (B; M. intestinales and Bacteroides thetaiotaomicron). The mucus is stained green while the bacteria are red.

Source: Reprinted with permission from Ng, K.M. and Torpini C./JoVE Journal, 2021

Microbes Eat Mucus

Microbes don't just live in mucus—they also munch on it. Various bacterial species rely on mucus as an important food source, and the capability to degrade mucins is relatively widespread across several bacterial phyla. Bacteria that metabolize mucin glycans for fuel release metabolic compounds and/or free up mucus components that support neighboring microbes. Such cross-feeding among bacteria helps shape microbial community composition, stability and resilience. Mucus-derived nutrients also trigger competition between diverse microbes—in the gut, some protists (i.e., single-cell, nucleus-harboring microbes) dine on mucin glycans. This drives trans-kingdom competition with commensal bacteria in ways that affect intestinal immunity, highlighting the ramifications of mucosal microbe-microbe interactions on host health.

Mucus Resists Pathogens…Except When it Doesn't

Among its other health-promoting features is the ability of mucus to impede colonization and infection by pathogens, including by actively attenuating bacterial virulence. For instance, in the opportunistic pathogen, Pseudomonas aeruginosa, mucus downregulates genes involved in quorum sensing, siderophore biosynthesis and toxin secretion, as well as dissolves bacterial biofilms. Mucosal microbial communities further hinder pathogen growth through direct antagonism, nutrient restriction and more. In other words, mucus provides the venue and fuel for commensal bacteria to resist their problematic counterparts.

Still, pathogens are not helpless, and they can circumvent, degrade and modify mucus to survive and thrive. For example, the gastric pathogen, Helicobacter pylori, increases the pH of gastric mucin, which reduces its viscoelasticity and allows the bacterium to move through the goop more easily. Some pathogens benefit from mucosal byproducts released by commensal organisms. Disrupting these metabolic relationships could be a viable therapeutic method for inhibiting pathogen colonization and expansion.

Bacteria harbor mechanisms of disrupting or evading the mucus layer to establish infection.

Source: Shen Y. H. and Hasnain S.Z./ Frontiers Cellular and Infection Immunity, 2021 under a CC BY 4.0 DEED license

Making the Most of Mucosal Microbes

The microbe-mucus interface is involved in the development of key host processes and structures, including metabolism, immune responses and even the thickness/composition of mucus itself! Alterations in the mucus layer have been tied to various diseases, including inflammatory bowel disease (IBD), cystic fibrosis, bacterial vaginosis, cancer and others. Accordingly, scientists are exploring how to harness host-microbe-mucus interactions to monitor and promote human health. 

Biotherapeutics

One area of research involves using mucus-dwelling microbes as live biotherapeutics. Various studies have shown that the gut bacterium, Akkermansia municiphila, which uses mucin as its main energy source, has multiple immunological and metabolic benefits, particularly in the context of metabolic disorders (e.g., obesity). For instance, a pilot study in volunteers who were overweight/obese and insulin-resistant found that administration of A. municiphila was safe and well-tolerated and improved certain metabolic parameters, like insulin sensitivity and plasma cholesterol levels. However, the organism can also be harmful depending on the context (e.g., enrichment in some hosts/immunological settings may lead to inflammation), highlighting the need to better understand when and how it should be used.  

Phage Therapy

There is also potential to exploit non-bacterial mucus residents, including bacteriophages (phages, or viruses that infect bacteria). Some phages can directly adhere to mucus, which increases their ability to contact and infect mucosal bacteria. This may benefit the host by limiting the number of bacteria present in the mucus. Specifically, phage mucus adherence can confer preventive protection against pathogens, pointing to the potential of prophylactic phage therapy for building a phage-mediated barrier to infection. Mucus-adhering phages may also be identified and/or engineered to selectively remove potentially pathogenic bacterial species from mucosal surfaces. Although mucus-phage-bacteria interactions have mostly been studied in the gut, scientists are also exploring their role and therapeutic applicability in other body regions, such as the lungs.

Some phages can bind intestinal glycans, creating a protective layer that can combat pathogens.

Source: Green S.L., et al./mBio, 2021

Glycan Detection

Mucosal microbes may also be useful for sensing mucus itself. Remember, mucus glycans provide a source of fuel for microbes and modulate community composition, among other functions. Moreover, mucus glycosylation patterns can differ in the context of diseases like IBD.

In a recent study, scientists reasoned that evaluating glycans in the gut could help identify disease biomarkers, therapeutic targets and inform methods for treating disease by shaping gut microbiota composition. With that in mind, they created transcriptional reporter strains of the gut bacterium, Bacteroides thetaiotaomicron, where each strain detects individual gut glycans. The scientists found that the reporters could detect mucosal glycan patterns in tiny volumes of gut mucus isolated from patients with IBD, and that these patterns differed from mucus sourced from healthy individuals. By expanding its application in other gut microbes, the reporter system could bolster understanding of gut mucus and identify host-microbe interactions critical for human health. 

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Want to learn more about how gut bacteria can be engineered to diagnose and treat disease? Check out this episode of Meet the Microbiologist with Maria Eugenia Inda-Webb.

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