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Page 14 of 23 Gutierrez et al. Microbiome Res Rep 2023;2:36 https://dx.doi.org/10.20517/mrr.2023.37

Several studies have found that Bifidobacterium species can limit the reduction of goblet cells and improve
the mucus barrier in the setting of chemically induced intestinal inflammation [Table 4]. For example,
B. bifidum, B. longum, B. longum subsp. longum, B. breve, and B. animalis subsp. lactis were shown to
increase MUC2, improve the mucus barrier, and ameliorate DSS-induced colitis [166-172] . A probiotic mixture
containing B. infantis was also shown to enhance the mucus barrier in DSS-treated mice . B. infantis and
[173]
B. breve were likewise found to limit the reduction of goblet cells in DSS models [174-176] , and B. lactis was
found to improve goblet cell counts in a zebrafish model of intestinal inflammation . Along the same
[177]
lines, B. dentium was also shown to increase MUC2, limit goblet cell reduction, and improve the mucus
layer in a TNBS-induced model of colitis . B. infantis and B. longum were also found to improve goblet cell
[96]
numbers in TNBS-induced colitis [176,178] , while B. animalis subsp. lactis restored goblet cell populations in
[179]
dinitrobenzene sulfonicacid (DNBS)-challenged mice . These studies indicate that Bifidobacterium species
can reduce goblet cell loss and mucus depletion in the setting of TNBS and DNBS-induced colitis.

Bifidobacterium species also have positive roles in modulating mucus in other inflammatory models. For
example, B. bifidum, B. infantis, and B. lactis increased MUC2 in the small intestine during LPS-induced
injury . In a rat model of necrotizing enterocolitis (NEC), B. bifidum was shown to increase mucin and
[180]
TFF3 expression and decrease the disease severity . B. longum EVC001 and B. infantis BB-02 also
[181]
decreased NEC occurrence in animals [182,183] . Even more promising is a double-blind, randomized, controlled
study of very-low-birth-weight preterm infants, in which a combination of B. breve strain Yakult and
L. casei strain Shirota completely prevented the occurrence of NEC in the intervention group, whereas 3.5%
of the cases developed NEC in control without probiotics . The mechanism by which Bifidobacterium
[184]
confers its benefits in NEC is not fully understood but may be similar to colitis involving the mucus layer,
intestinal permeability, and inflammation.

Rotavirus gastroenteritis is another disease where Bifidobacterium species have been shown to beneficially
modulate the mucus layer. B. bifidum G9-1 was shown to increase MUC2, normalize mucin-positive goblet
cells in the small intestine, and reduce the incidence, diarrheal scores, and intestinal damage in the
supplemented group with rotavirus compared to the control group with rotavirus alone . B. infantis PCM
[185]
has also been shown to maintain goblet cells and reduce epithelial damage in the small intestine of mice
infected with the pathogen Cronobacter sakazakii . These data demonstrate that goblet cells and mucin
[186]
production are also beneficially influenced by bifidobacteria in the small and large intestines in multiple
inflammatory models.

Pro-inflammatory cytokines have been shown to negatively regulate goblet cells, while anti-inflammatory
compounds such as IL-10 are known to alleviate ER stress and enhance goblet cell function. Another
pathway by which Bifidobacterium species positively modulate goblet cells is through the modulation of
intestinal cytokines [Table 5]. In TNBS-induced colitis mouse models, supplementation of B. infantis,
B. breve, and probiotic cocktail mixes that included B. longum Bar 33 and B. animalis subsp. lactis Bar 30
resulted in reduced levels of several pro-inflammatory cytokines, e.g., IL-2, IL-1β, IL-13, IL-12p40, IL-17A,
IL-21, IL-23, IFN-γ, TNF-α, and MCP-1, relative to the untreated TNBS groups [170,176,178] . These strains
additionally led to rises in the anti-inflammatory cytokine IL-10 [170,176,178] . Similarly, B. dentium reduced
serum IFN-γ, IL-1α, IL-1β, IL-12, and TNF-α with a concomitant increase in IL-10 in comparison to the
[96]
TNBS control mice . Another study using DSS revealed that B. breve and B. longum lowered both systemic
and colonic levels of TNF-α, IL-1β, and IL-6 . These studies suggest that in addition to directly
[171]
modulating goblet cells through metabolites and suppression of ER stress, Bifidobacterium strains may be
indirectly modulating goblet cell function via immune regulation.