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Page 2 of 23 Gutierrez et al. Microbiome Res Rep 2023;2:36 https://dx.doi.org/10.20517/mrr.2023.37

primary structural component of intestinal mucus is a gel-forming glycoprotein called MUC2. MUC2 is a
large, heavily glycosylated protein that forms disulfide-bonded dimers. These dimers undergo further
polymerization and crosslinking, resulting in the formation of a gel-like network that constitutes the mucus
layer.

In addition to the gel-forming MUC2, intestinal mucus contains a diverse array of compounds that
contribute to its composition and functionality. Mucus harbors Antimicrobial Peptides (AMPs): small
cationic peptides that possess antimicrobial properties. AMPs in the mucus layer help to maintain the
balance of microbial populations by inhibiting the growth of pathogenic bacteria and promoting the growth
of beneficial commensal bacteria. Immunoglobulin A (IgA) antibodies are also abundant in the mucus layer
of the gut. They are produced by specialized immune cells called plasma cells and secreted into the mucus,
where they play a crucial role in immune defense by neutralizing pathogens, preventing their adherence to
the intestinal epithelium, and promoting their clearance from the gut. In addition to MUC2, goblet cells also
secrete trefoil factors, a family of small peptides that contribute to the maintenance of mucosal integrity and
repair by promoting epithelial cell migration, enhancing wound healing, and providing protection against
injury and inflammation. Other mucus-associated proteins, such as FCGBP, metalloenzyme CLCA1, ZG16,
Lypd8, glycosaminoglycans, and chitinases, contribute to the structural organization, hydration, and
[1]
stability of the mucus layer . These compounds play various roles in shaping the mucus layer and
modulating host-microbe interactions within the gut.

The structural organization of intestinal mucus is highly dynamic, exhibiting regional variations along the
gastrointestinal tract. In the small intestine, the mucus layer is thinner and less firmly attached to the
epithelium, allowing for efficient absorption of nutrients. In contrast, the mucus layer in the colon is thicker
and firmly adheres to the epithelial surface, serving as a physical barrier that limits direct contact between
luminal contents and the epithelium. In the colon, the mucus layer is stratified, consisting of two distinct
regions: the inner mucus layer and the outer mucus layer. The inner mucus layer, also known as the firmly
adherent mucus layer, is in direct contact with the intestinal epithelium. It is tightly packed with MUC2,
forming a dense and organized matrix that provides a protective barrier against luminal contents. The outer
mucus layer, also referred to as the loose mucus layer, is less compact and acts as a reservoir for commensal
bacteria and other luminal components. This outer layer is more penetrable and allows for the
establishment of symbiotic interactions between the gut microbiota and the host.

One feature of mucus that makes it amenable to microbe interactions is the structure of the mucin proteins.
[2-7]
The MUC2 protein is extensively O-glycosylated with branched oligosaccharides . O-glycans are attached
at serine and threonine residues in the MUC2 protein and consist of core structures of α- and β-linked
N-acetyl-glucosamine, N-acetyl-galactosamine, and galactose. The core structures are then elongated and
generally modified by α-linked fucose, sialic acid, and sulfate residues . Mucin glycoproteins serve as both
[4]
an adhesion site and nutrient source for the resident gut microbes, providing an array of complex microbe-
host interactions.

Bifidobacteria and mucus
Among the bacteria found in the gut microbiota, Bifidobacterium species are known to reside within the
intestinal mucus layer [8-14] and exert multiple beneficial effects on the host [15-20] . Bifidobacteria are Gram-
positive anaerobic bacteria from the phylum Actinobacteria that can have a rod or a distinctive bifid (i.e., Y)
shape. There are currently 55 recognized species and subspecies of Bifidobacterium [21-23] . These species can
be grouped into seven phylogenetic clusters: B. longum, B. adolescentis, B. pseudolongum, B. boum,
B. asteroides, B. pullorum, and B. bifidum.