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Page 10 of 23 Gutierrez et al. Microbiome Res Rep 2023;2:36 https://dx.doi.org/10.20517/mrr.2023.37

level of freed mucin-derived O-glycans was negatively correlated with populations of Bifidobacteriaceae,
indicating that mucus degradation was not occurring at the same level in B. longum supplemented
[119]
infants . Along the same lines, genes involved in mucus-degrading pathways, particularly in carbohydrate
metabolism, in Bifidobacterium species were found to be expressed to a greater degree in formula-fed
infants than in breast-fed infants . It has been speculated that HMOs, which are similar to mucus in some
[120]
of the glycan structures [120,121] , or other mucin-like glycoproteins present in breast milk, may compete with
intestinal mucus as a substrate .
[118]

In addition to being found in infants, mucus-degrading Bifidobacterium species are present in adults and
have been linked to the suppression of detrimental mucus degradation. One example of excessive mucus
degradation that may be prevented by Bifidobacteria is in the context of a Westernized diet, a diet
characterized by low fiber but high fat and sugar. It has been demonstrated in mice harboring defined
microbial communities that consuming a Westernized diet leads to an expansion of mucin-degrading
bacteria such as Akkermansia muciniphila and Bacteroides caccae, and this shift enables the bacterial
community to target the mucus layer for digestion in lieu of dietary fibers . In a model with complex
[122]
native gut microbiota, mice fed a Westernized diet similarly exhibited an expansion of Akkermansia and a
corresponding decrease in Bifidobacterium species and increased susceptibility to pathogens and
[123]
inflammation. In this setting, the addition of B. longum NCC 2705 or the prebiotic inulin resulted in
elevated levels of endogenous Bifidobacterium species, reduced mucus degradation, and restored the mucus
barrier. In a similar vein, B. bifidum G9-1 was shown to protect against mucus degradation by
[124]
A. muciniphila following small intestine injury caused by a proton pump inhibitor and aspirin . Another
study found that the administration of B. pseudolongum Patronus increased mucosal thickness in rats and
decreased the levels of A. muciniphila . These data suggest that mucus degradation by Bifidobacterium
[125]
species is not detrimental to the host and that Bifidobacterium species keep mucus degradation in check.

MUCUS MODULATION BY BIFIDOBACTERIUM SPECIES
Modulation of mucus by Bifidobacteria in homeostasis
Although some bifidobacteria have mucolytic properties, they generally have an overall positive net effect in
regulating intestinal mucus. Several studies have found that Bifidobacterium species elevate mucus levels in
vitro and in vivo [Table 3 and Figure 2]. In vitro, B. infantis, B. breve, B. longum and a probiotic cocktail
containing these microbes and others (VSL#3) was found to stimulate mucus secretion in human mucus-
producing LS174T cells . The probiotic cocktail was also found to increase MUC2 expression and
[126]
secretion in rat colonic loops . In another study, B. dentium was reported to increase MUC2 in human
[126]
[18]
mucus-producing T84 cells . Short-chain fatty acids (SCFA) have been demonstrated to increase MUC2
expression , and Bifidobacterium species are known to produce high levels of SCFA acetate. The
[127]
application of acetate was likewise able to increase MUC2 gene and protein levels in T84 cells . In vivo,
[18]
B. dentium was found to colonize germ-free mice, elevate intestinal acetate levels, and increase MUC2 at the
gene and protein levels . An elevated number of goblet cells and goblet cell-specific genes were observed in
[18]
[18]
B. dentium mono-associated mice, as well as increased mucin glycosylation . In this model, it was
speculated that B. dentium-generated gamma-aminobutyric acid (GABA) was able to activate autophagy
and calcium signaling to stimulate the release of mucus from goblet cells and bolster the mucus barrier . In
[18]
addition to B. dentium, B. bifidum and B. longum colonize germ-free mice and increase intestinal mucin
glycoproteins [128,129] . These studies using mono-associated gnotobiotic animals provide very powerful
evidence that B. dentium, B. bifidum and B. longum can modulate goblet cell function and increase mucus
production. In mice with complex gut microbiota, B. breve supplementation led to 3,996 upregulated and
[35]
465 downregulated genes in supplemented neonatal mice relative to the untreated group . Upregulated
genes in the neonatal mice encoded multiple mucus layer-associated proteins such as MUC2. These data
suggest that B. breve in early life modulates goblet cells. In adult mice, administration of a probiotic cocktail