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Gutierrez et al. Microbiome Res Rep 2023;2:36 https://dx.doi.org/10.20517/mrr.2023.37 Page 15 of 23

OVERALL EFFECTS OF BIFIDOBACTERIUM-MUCUS INTERACTIONS ON THE HOST
The literature suggests that the intestinal mucus layer plays a crucial role in the interaction of
Bifidobacterium species with the host. It appears that the majority of Bifidobacterium species bind to
intestinal mucus and establish a unique niche that affords them an advantageous position for their
beneficial activities. Within the mucus layer, some Bifidobacterium species can degrade mucus, while others
must rely on other nutrient sources. In the mucus layer, Bifidobacterium species likely perform the
following functions: (1) exclude pathogens; (2) cross-fed commensal bacteria; (3) limit excessive mucus
degradation; (4) secrete compounds such as acetate, which elevate MUC2 expression and increase mucus
production; (5) reduce goblet cell ER stress; (6) limit inflammation- and infection-driven goblet cell loss; (7)
suppress pro-inflammatory cytokines; and (8) increase anti-inflammatory pro-goblet cell IL-10.

The literature points to the capacity for Bifidobacterium species to beneficially modulate goblet cell number
and function, thereby regulating the mucus layer and intestinal barrier function. This modulation of the
goblet cells by Bifidobacterium is likely even more important during the setting of infection and
inflammation. Through these interactions, Bifidobacterium species facilitate a dynamic interplay that
contributes to gut homeostasis and overall host health.

LIMITATIONS AND GAPS IN THE FIELD
While these findings are compelling, there are still several gaps in knowledge. First, it is unclear which
Bifidobacterium strains are the most effective at positively regulating goblet cell function. Very few studies
have performed head-to-head comparisons of different Bifidobacterium strains and studies vary in terms of
mouse strain (C57B6/J, BALBc, Swiss Webster, etc.), colonization status (mono-association, gnobotioic with
defined communities, conventional, etc.), and challenge (TNBS, DSS, DNBS, LPS, infection etc.). These
variables make it difficult to tease out the nuances between strains and effects. Second, the metabolites that
drive goblet cell-specific attributes of Bifidobacterium are not well characterized. It is well documented that
Bifidobacterium species can generate acetate and this SCFA can elevate MUC2 levels, but it is likely that
other metabolites also stimulate MUC2. In addition to modulating MUC2 levels, Bifidobacterium species
can influence goblet cells in other ways, such as suppressing ER stress, promoting autophagy, and
stimulating mucus expulsion. Likewise, it is not clear how bifidobacteria members regulate IL-10
production, which could indirectly affect goblet cell homeostasis. These pathways need to be explored with
multiple Bifidobacterium strains.

The advent of intestinal organoids is a promising new technology to address Bifidobacterium-goblet cell
interactions. This model maintains segment specificity, is not immortalized, and is not cancer-derived.
Importantly, intestinal organoids harbor MUC2-positive goblet cells and have been previously used to
examine bacterial-host interactions, including Bifidobacterium [95,187-189] . We anticipate that many future
studies will employ this model to define the mechanisms by which Bifidobacterium species regulate goblet
cells and interact with intestinal mucus.

Although there are still large gaps in the field, the wealth of literature allows us to make some key
observations on conserved bifidobacteria functions, such as mucus binding, suppression of inflammation-
driven goblet cell depletion, and elevation of MUC2. Understanding the interaction between
Bifidobacterium and the intestinal mucus layer is imperative for unraveling the mechanisms underlying
their beneficial effects. With this knowledge, there is immense potential for developing targeted therapeutic
interventions.