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Sharma et al. Microbiome Res Rep 2024;3:3 https://dx.doi.org/10.20517/mrr.2023.51 Page 3 of 17

in the gut microbial diversity can cause health problems. In order to balance the altered gut microbiota,
various strategies including the use of probiotics, prebiotics, postbiotics, antibiotics, and fecal microbiota
transplantation have been used. Bifidobacteria, recognized as a highly effective probiotic, offers numerous
benefits to the host. According to the International Scientific Association for Probiotics and Prebiotics
(ISAPP), probiotics can be defined as “live microorganisms that, when administered in adequate amounts,
[13]
confer a health benefit on the host” . Various mechanisms through which bifidobacteria exert benefits to
the host include colonizing the gut, modulating the immune system, competitive exclusion of pathogens,
antimicrobial and bactericidal activity, metabolite production, and regulating the gut epithelial barrier
[Figure 1].

Colonizing the gut
Colonization inside the gut is the primary and most significant mechanism of bifidobacteria in maintaining
gut homeostasis. Bifidobacteria colonize the gut using various indigenous and exogenous factors. Prolonged
adhesion to the gut epithelium is required for successful colonization, and several factors such as
exopolysaccharides (EPS), lectins, adhesion molecules, and lipoproteins play an important role in this
adhesion mechanism. These factors can help facilitate the binding of bifidobacteria to gut epithelium by
working as “adhesion promoter”. These factors can be modified or exploited in such a way to increase the
binding of the bifidobacteria to the intestinal epithelium. Increased expression of lipoprotein and BopA has
been reported, which is significantly responsible for the adhesion of B. bifidum MIMBb75 to Caco-2 cells .
[14]
It has also been seen that human milk oligosaccharide and a probiotic contributed to the binding of
B. longum infantis ATCC 15697 to Caco-2 cells and HT-29 cells . Colonization by fimbrial attachment of
[15]
certain strains like B. longum subsp. longum is also reported. Gene clusters responsible for pili synthesis
have been identified in certain bifidobacterial strains like B. breve and B. bifidum. In B. breve UCC2003, a
type IVb tight adherence (Tad) gene cluster has been identified, which enhanced the adhesion to the gut
epithelium in murine models . Exogenous factors like prebiotics can also enhance the adhesion of
[16]
bifidobacteria inside the gut. Prebiotics can increase the survival rate of Bifidobacterium probiotics in the
[17]
gut, which can, in turn, promote their growth . Sometimes, exopolysaccharides also facilitate the adhesion
of bifidobacteria to the gut epithelial wall. Studies have reported a correlation between the adhesion of
bifidobacterial strains and EPS production. B. breve A28 produces higher levels of EPS, which is responsible
[18]
for its firm adhesion to the intestinal cell lines .
Modulating the immune system
Immunomodulatory effects of bifidobacteria exert various benefits to the host, and it is by far the most
important mechanism by which bifidobacteria maintain gut homeostasis. Chiu et al. in 2014 published a
study which showed that B. adolescentis DB-2458 and B. longum subsp. infantis GB-1496, which were
isolated from human breast milk, shows a robust immunomodulatory effect via Th1/Th2-related cytokine
[19]
regulation . It has been seen that B. breve CNCM1-4035 and its culture supernatant can enhance the
immune response of human intestinal dendritic cells via TLR signaling pathways against Salmonella enterica
typhi. This can be attributed to the upregulation of TLR9 gene transcription, speculating that the TLR9
signaling pathway is responsible for robust anti-inflammatory effects against Salmonella . B. animalis
[20]
subsp. lactis BB-12 can reduce the proinflammatory cytokine secretion in adults by downregulating the
TLR-2 expression . In the case of cigarette smoking-induced immune response, B. breve M-16V and
[21]
L. rhamnosus are known to suppress it when used in combination. In human THP-1 macrophage, a
combination of B. breve M-16V and L. rhamnosus probiotics could suppress the expression of IL-1β, IL-6,
IL-10, IL-23, TNF-α, and CXCL-8 along with TLR4, TLR9, and NF-κB signaling pathways which are mainly
induced by cigarette smoking . Apart from this, animal studies have shown that intestinal cells that were
[22]
treated with B. longum, B. infantis, and B. youth can decrease the expression of TLR-2 and TLR-4. These
three strains also enhanced the gut epithelial barrier functions .
[23]