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Page 8 of 23 Gutierrez et al. Microbiome Res Rep 2023;2:36 https://dx.doi.org/10.20517/mrr.2023.37

mucin-binding partners. B. bifidum possesses two sortase-dependent pili that promote bacterial
[76]
coaggregation and bind to mucus-producing Caco-2 cells . Another study found that B. bifidum produces
an extracellular sialidase that mediates adhesion to mucus via a conserved sialidase domain peptide that
[77]
interacts with mucin carbohydrates . Similar to B. bifidum, B. longum also expresses multiple mucus-
binding proteins. B. bifidum and B. longum both have been shown to express extracellular transaldolases
that function as an adhesin that is capable of binding mucin [78,79] . A recent study found that B. longum
harbors 21 putative adhesion proteins . Using an overexpression system in a heterologous host, it was
[75]
found that FimM exhibited significant adhesion to mucus-producing LS174T goblet cells, and it was further
found that mucin was one of the major adhesion receptors for the FimM protein . Homologs of FimM
[75]
were also identified in B. bifidum, B. gallinarum, and 23 other B. longum strains by sequence similarity
analysis. Another study found that B. longum harbors a protein with high homology to type 2 glycoprotein-
binding fimbriae that may mediate mucus adhesion . B. longum additionally produces the moonlighting
[80]
proteins EF-Tu and enolase, which indirectly promote adhesion to mucus-producing Caco-2 cells through
interactions with host plasminogen . Likewise, enolase plays the role of an adhesion factor in B. lactis
[81]
Bl07 , and GroEL is another moonlighting protein that has been indicated as an adhesion factor for
[82]
B. animalis subsp. lactis .
[83]
As another example of the various adhesins employed by Bifidobacterium species, B. longum was found to
possess a 26-amino-acid peptide called Blap-1 that mediates adhesion to HT-29 cells. Interestingly, genomic
analysis revealed that Blap-1 was an identical match to a site in a large extracellular transmembrane protein
[84]
encoded by the BL0155 open reading frame of B. longum NCC2705 . Additionally, B. longum possesses an
endo-α-N-acetylgalactosaminidase that contains binding sites specific to the protein core of mucin
glycoproteins . Furthermore, the genome of B. longum subsp. infantis encodes several family 1 of solute
[85]
binding proteins (F1SBPs), and these proteins were shown to bind and transport mucin
oligosaccharides [86,87] . In addition to B. bifidum and B. longum, B. breve has type IVb pilus-type proteins that
facilitate colonization in the host gut [82,83,88] . Interestingly, it has also been shown that B. longum produces
extracellular vesicles that export mucin-binding cytoplasmic proteins, and these proteins promote the
adhesion of B. longum to mucus . It has also been recently shown that the polyamine Spermidine
[89]
[90]
significantly increased the adhesion of B. bifidum Bb12 to mucus isolated from healthy infants , suggesting
that secreted factors could also influence the adherence of Bifidobacterium to mucus. Together, these studies
indicate that although multiple Bifidobacterium species can bind to mucus, the mechanisms of adhesion
appear to be diverse, even among strains of the same species.

The structure of mucus likely dictates the consequences of mucus binding for Bifidobacterium species. In
the small intestine, the mucus is loose and not attached to the epithelium. As a result, mucus adhesion likely
does not promote persistent colonization of the small intestine. In contrast, in the colon, the mucus is highly
organized and adhesion to colonic mucus most likely allows Bifidobacterium species to persist and colonize
the colon. The adhesion of Bifidobacterium to colonic mucus is also thought to increase the transit time of
the bacteria in the gut, thereby maximizing its beneficial properties [91,92] . It has also been shown that
colonization of the mucus layer by Bifidobacterium species positively regulates goblet cells. These
interactions are all viewed as beneficial for the host. As a result of these positive attributes, the ability to
adhere to human intestinal mucus is a commonly employed criterion for the selection of probiotic
organisms [75,93,94] .

The binding of Bifidobacterium to intestinal mucus extends beyond a mere physical attachment; it serves as
a gateway for host-microbe crosstalk. By positioning themselves within the mucus, Bifidobacterium strains
gain proximity to host cells, enabling the effective delivery of health-promoting molecules, metabolites, and