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Gutierrez et al. Microbiome Res Rep 2023;2:36 https://dx.doi.org/10.20517/mrr.2023.37 Page 3 of 23

Bifidobacteria are predominant in the healthy breast-fed infant gut due to the presence of human milk
oligosaccharides (HMOs), which these bacteria are adept at utilizing [24-27] . Studies have suggested that
Bifidobacterium species make up ~80% of a breast-fed infant gut microbiota [28-32] . The benefits of
Bifidobacterium strains are especially pronounced in early life, encompassing epithelial maturation, immune
cell activation, and gut-brain-axis crosstalk [33-39] . Upon the introduction of solid food and weaning, the level
of intestinal bifidobacteria continually decreases until adulthood, at which point bifidobacteria are
maintained at a relative abundance of about ~10% throughout adult life [31,40-42] . In the elderly, the level of
[42]
bifidobacteria further diminishes to about 0%-5% relative abundance . This reduction in bifidobacteria
levels in the elderly has been linked to age-related alterations in lifestyle and environment. Interestingly, this
decline in Bifidobacterium abundance coincides with a simultaneous decrease in the thickness of intestinal
mucus and an increase in its permeability [43-45] . It remains uncertain whether there is a direct link between
decreased Bifidobacterium and decreased mucus, but this interesting observation suggests a relationship.
Independent of age, Bifidobacterium species can be found in both the small intestine and colon, although
they exhibit a higher abundance in the colon. Several Bifidobacterium species have been observed to interact
with intestinal mucus, colonize the mucus layer, consume mucus glycans, and exert strain-specific
modulatory effects on the mucus layer. This review covers the existing literature for the following
Bifidobacterium-mucus interactions: (1) mucus adhesion; (2) mucin glycan degradation; (3) positive
modulation of goblet cell cells; (4) goblet cell retention during inflammation; and (5) suppression of pro-
inflammatory cytokines and production of anti-inflammatory IL-10.

MUCUS ADHESION BY BIFIDOBACTERIUM SPECIES
Multiple studies have demonstrated the ability of Bifidobacterium species to adhere to mucus [Table 1].
B. adolescentis, B. angulatum, B. bifidum, B. breve, B. catenulatum, B. infantis, B. longum, B. infantis,
B. animalis subsp. lactis, and B. pseudocatenulatum have all been shown to bind to mucus isolated from the
stool of human infants and/or adults [46-51] . B. bifidum, B. breve, B. animalis, B. animalis subsp. lactis,
B. longum, B. longum subsp. infantis, and B. catenulatum have also been demonstrated to bind to intestinal
mucus isolated from the healthy part of resected colonic tissue [52-58] .

Interestingly, Bifidobacterium animalis subsp. lactis and unclassified Bifidobacterium species were shown to
adhere well to mucus isolated from the feces of newborns, 2-month-old infants, 6-month-old infants, and
adults (25 to 52 years), but had substantially lower adhesion to mucus derived from the feces of elderly
[41]
individuals (74 to 93 years) . It was also found that B. animalis subsp. lactis had diminished adhesion to
[50]
mucus isolated during episodes of diarrhea . These findings point to the integrity of mucus for adhesion.
In addition to human stool and tissue derived mucus, B. dentium, B. bifidum, B. adolescentis, B. breve,
B. pseudocatenulatum, B animalis subsp. lactis, B. longum, and B. infantis have been shown to bind to
human mucus-producing HT29-MTX, Caco-2, INT-407, and LS-174T cells [53,59-69] as well as to cecal mucus
from germ-free mice and rats [18,65] [Table 1]. B. adolescentis, B. angulatum, B. longum, B. infantis,
B. pseudocatenulatum, B. bifidum, B. breve, B. catenulatum, and B. animalis subsp. lactis were also found to
bind to pig stomach mucus [48,70] , and B. animalis subsp. lactis was reported to bind to pig intestinal
[71]
mucus . In agreement with these findings, Bifidobacterium species were found to have widespread
adhesion to mucin gels created with pig stomach mucus in a bioreactor model . These studies indicate that
[72]
mucus adhesion is widely conserved among Bifidobacterium species.

The binding of Bifidobacterium to intestinal mucus is regulated by diverse adhesins [Figure 1].
Bifidobacterium species employ pili, surface adhesion proteins, moonlighting proteins, and other surface-
anchored proteins to adhere to intestinal mucus [Table 2] [73-75] . For example, B. bifidum has several known