Relationship Advice from Mucus


Breaking down the microbiology world one bite at a time

Relationship Advice from Mucus

A love-hate relationship

The human gut is home to trillions of bacteria. These microbial inhabitants are necessary for our health. They help us digest the food we eat, educate our immune systems so that we may better respond to assaults by pathogens, and communicate with our brains to help maintain cognitive homeostasis. Nevertheless, nurturing this seemingly harmonious relationship takes a lot of effort. Effective host-microbe symbiosis, like any relationship, requires balancing cooperative communication with healthy boundaries. We want to talk to our microbes, but we don’t want them so close to us that our bodies try to fight them off. If they come too close, our immune systems will get activated and cause excessive inflammation. Nobody wants that. So, how do our bodies carve out a boundary that ensures we are able to interact with our microbial residents, but they don’t come close enough to result in an active immune response?

The answer lies in an oft-unloved word: mucus!

Figure 1. Separating us from our bugs. The mucus barrier separates our cells from our gut microbes. The mucus layer is made up of glycoproteins, called mucins, that form a matrix-like structure (figure made using Bioicons and Adobe Illustrator).

Keeping our bugs at bay with mucus

To keep our microbes at bay, our intestinal cells secrete a layer of mucus that acts as a physical barrier against microbes. Mucus is a gel-like structure that is primarily made up of glycoproteins (proteins attached to sugar molecules) called mucins (Figure 1). Mucosal layers are found at most “barrier sites”:parts of the body that are in contact with the external environment, including our respiratory and digestive tracts. This protective layer acts as a physical barrier, preventing microbes from invading our systems. However, mucus is not just a “stay-out” sign for the microbes in the gut, it can also serve as a source of nutrition for them. Bacteria can chew on mucin sugars using enzymes (called mucinases) to obtain energy. Thus, host-microbe symbiosis is actively maintained at our mucosal layers.

As you can imagine, if our microbes get greedy and chew up too much of our mucus layer, it will become thinner and patchier. This barrier breach will allow microbes to pervade our system more easily, causing inflammation. Clearly, the mucus must maintain a balance between feeding our gut bacteria while keeping them at arm’s length. But how does it strike this balance? A recent study by Yao and colleagues hints at a possible answer: sialylation! 

Figure 2. Sialic acid saves the day. Our mucus is stabilized by ST6, an enzyme that adds sialic acid molecules on the sugars that make up mucin. This chemical modification protects mucins from degradation by bacterial enzymes (figure made using Bioicons and Adobe Illustrator).

Stabilizing our mucus by adding sialic acids

Sialylation is the addition of a molecule of sialic acid onto mucin glycoproteins. Yao et al., show that when a sialic acid molecule is attached to mucins by an enzyme called ST6, these proteins are protected from degradation by bacterial enzymes (Figure 2). The authors discovered this by mixing MUC2, the predominant mucin in gastrointestinal mucus, with a mucinase from E. coli in the presence or absence of ST6. When ST6 is missing, the mucins are not sialylated. In this scenario, they noticed increased MUC2 degradation, implying that sialylation is necessary to protect mucins from becoming bacterial food. In this way, our cells can use this modification to make sure that our mucus layer stays intact. This enzyme, ST6, can regulate the proportion of our mucins that can be chewed up by our bacteria, thus helping maintain host-microbe symbiosis.

Defects in sialylation associated with inflammation

After understanding how ST6 can help balance the microbe-host relationship, the authors investigated whether this finding is relevant to human health. They screened worldwide cohorts of patients with inflammatory bowel disease (IBD), a series of disorders that result in chronic intestinal inflammation. Interestingly, they found germline ST6 mutations in individuals with early-onset IBD. Authors generated mouse models by introducing the ST6 mutations identified in human patients into mouse germlines. These mouse models recapitulated the authors’ hypotheses; ST6 mutant mice had reduced mucin sialylation, increased gut microbiota invasion of intestinal mucus, and more severe colon inflammation. When these mutant mice were fed non-mutated mucins, the symptoms vanished! The mice now had thickened mucus barriers and a marked reduction of inflammation, further validating that ST6 is essential for ensuring that the mucus is perfectly balanced between protection against invasion and providing nutrition to our gut microbiomes (Figure 3).    

Figure 3. Sialylation protects from inflammation. Mice with mutated ST6 have unsialylated mucus, which results in excessive mucus degradation by gut bacteria,  bacterial invasion of the barrier, and intestinal inflammation. When fed sialylated mucin from non-mutant mice, the ST6 mutants show reduced inflammation indicating that ST6 deficiency can be rescued by the addition of sialylated mucin (figure made using Bioicons and Adobe Illustrator).

Mucus: a bacterial friend and foe

Our mucosal barrier is the first line of defense against pathogens in the gut. However, it is also home to a rich diversity of gut microbes that help us in myriad ways. In this study, the authors established a pathway that helps regulate the relationship with our gut bacteria. Using this mechanism, our intestinal cells can control how much of our mucus is fighting versus feeding our microbes. This perfect balance makes mucus an expert in maintaining symbiosis. Its relationship advice? Stay flexible, balanced, and always sialylated!

Learn More:

  1. Read this to get a primer on how mucus is produced.
  2. Learn how mucus switches between fighting and feeding our microbes in this review.
  3. Dig deeper into the importance of mucus in inflammatory bowel diseases here.

Link to the original post: Yao, Y., Kim, G., Shafer, S., Chen, Z., Kubo, S., Ji, Y., Luo, J., Yang, W., Perner, S. P., Kanellopoulou, C., Park, A. Y., Jiang, P., Li, J., Baris, S., Aydiner, E. K., Ertem, D., Mulder, D. J., Warner, N., Griffiths, A. M., Topf-Olivestone, C., … Lenardo, M. J. (2022). Mucus sialylation determines intestinal host-commensal homeostasis. Cell, 185(7), 1172–1188.e28.

Featured image: Created by author using Bioicons and Adobe Illustrator.