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against colon carcinoma, exerting anti-carcinogenic activity and ultimately regulating gut homeostasis [36,37] .
The anti-carcinogenic role of vitamin B12 and folates produced by bifidobacteria is also explored.
Polysaturated fatty acids produced by probiotic bifidobacterial strains participate in gut homeostasis by
exerting anti-carcinogenic, anti-diabetic, and anti-inflammatory properties [37,38] .

Regulating the gut epithelial barrier
Human gut epithelium harbors the largest site for the interaction between the outer environment and the
host milieu. It comprises the outermost layer of mucous followed by an internal layer of epithelial cells and
innermost lamina propria. The layer of epithelial cells contains tight junctions, which are responsible for
maintaining the integrity of the gut epithelium . Bifidobacteria play a prominent role in maintaining gut
[38]
integrity. Studies with human intestinal cell models Caco-2 have shown that upon administration of
Bifidobacterium, downregulation in the expression of certain proinflammatory cytokines was seen, which
8
enhanced the transepithelial electrical resistance. 10 CFU dose of Bifidobacterium can increase the
expression of several tight junction proteins, including claudins, ZO-1, and occluding. Bifidobacteria can
also enhance the activity of tight junctions by targeting the TLR2 pathway [39-41] . In addition to this, they can
prevent the prolonged adhesion of pathogens by secreting a thick layer of mucus that is constantly being
replaced. Certain bifidobacteria species can also prevent the TNF-α mediated disruption of the epithelial
[42]
barrier .
BIFIDOBACTERIUM AND CANCER: AN UNEXPLORED CONTROVERSY
As mentioned earlier, the gut microbiota of an individual keeps changing with age and it also gets affected
by a variety of factors. However, any major change in the diversity of gut microbiota, known as “gut
microflora dysbiosis”, may lead to major consequences in terms of developing various diseases. It has been
reported that any chaotic shift in the abundance of bifidobacteria also results in developing atopic diseases,
irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colorectal cancer (CRC), celiac diseases,
and sometimes obesity . Several studies have shown both the direct and indirect involvement of
[43]
bifidobacteria in carcinogenesis. This controversial role of bifidobacteria is discussed below in this article.

Bifidobacterium and gastric cancer
According to the Global Cancer Observatory (GLOBOCAN) data from the year 2020, gastric cancer
occurrence ranks fifth and is the fourth most lethal malignancy worldwide . According to Lauren’s
[44]
classification, gastric cancer has two subtypes: diffuse and intestinal. The intestinal type of gastric cancer
shows a better prognosis where malignant cells are arranged in a glandular fashion and also have adhesive
properties. On the contrary, the diffuse type of gastric cancer shows a very poor prognosis, with tumor cells
[45]
being scattered in the stomach as they have non-adhesive properties . A research study reported in the
year 2021 showed the gut microflora diversity in patients with gastric carcinoma with its subtypes, patients
[46]
with gastrointestinal stromal tumors (GIST), and healthy controls in Finland . It was seen that gastric
adenocarcinoma patients had the lowest gut microflora diversity than GIST patients and healthy control.
Upon the diversity analysis of diffuse and intestinal-type gastric adenocarcinoma compared with GIST and
healthy control, they found that only the diffuse subtype had a significantly lower abundance of the
bifidobacteriaceae family . In mice models, it was previously reported that a lower abundance of gut
[46]
resident Bifidobacterium is linked with more aggressive tumors . Hence, we can postulate that lower
[47]
Bifidobacterium levels are associated with more aggressive gastric malignancies.

The most common risk factor for gastric cancer is Helicobacter pylori infection. H. pylori was declared a
class-I carcinogen by the International Agency for Research on Cancer (IARC) in the year 1994 . H. pylori
[48]
infection is responsible for developing gastric diseases such as gastric cancer, gastric ulcer, and duodenal