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Procaccianti et al. Microbiome Res Rep 2023;2:24 https://dx.doi.org/10.20517/mrr.2023.23 Page 3 of 12

[40]
association with immunochemoresistance and treatment failure [Figure 1].

In this review, after summarizing the relationship between GM and immunochemotherapy, we discuss the
latest research evaluating the impact of the presence of Bifidobacterium in the GM of cancer patients, as well
as its administration in probiotic formulations on therapeutic response and key clinical outcomes. Finally,
we stress the need to conduct further studies, especially of a functional nature, in order to move from purely
associative observations to mechanistic glimpses, which provide robust experimental evidence on the role of
Bifidobacterium in the anticancer immunochemotherapy landscape. The definition of this role will make it
possible to improve current intervention strategies for truly successful precision medicine approaches.

THE RELATIONSHIP OF THE GUT MICROBIOME WITH RESPONSE TO
IMMUNOCHEMOTHERAPY
In recent years, several studies have highlighted a bidirectional relationship between GM and
immunochemotherapy in different types of cancer. Indeed, therapeutic efficacy was significantly reduced in
the absence of GM, thus suggesting that commensal microbes may modulate anticancer immune responses
through several mechanisms [40,41] . The first example of this intricate interconnection between gut microbes
and anticancer treatment involves cyclophosphamide, an approved chemotherapeutic drug. It has been
shown that cyclophosphamide can alter GM composition in mice and promote the translocation of specific
Gram-positive bacteria into secondary lymphoid organs, stimulating the production of Th17 cells [42,43] .
Indeed, germ-free mice or mice treated with broad-spectrum antibiotics showed resistance to
[43]
cyclophosphamide-based therapies . In particular, the antitumor response was associated with increased
levels of Lactobacillus johnsonii, Enterococcus hirae and Barnesiella intestinihominis . A few years later,
[43]
elegant work by Daillere et al. revealed the mechanisms by which E. hirae and B. intestinihominis were able
to stimulate the immune response against tumor cells . The former translocated from the small intestine to
[44]
secondary lymphoid organs and increased the intratumor CD8/Treg ratio, while the latter was
overabundant in the colon where it promoted the infiltration of interferon-gamma (IFN-γ)-producing T
cells into cancer lesions. Further confirming these findings, the antitumor activity of cyclophosphamide was
restored in murine models receiving an oral gavage of E. hirae after antibiotic treatment.

GM can also modulate the efficacy of immunotherapy [45-47] . Since their development, immune checkpoint
inhibitors have revolutionized the anticancer therapeutic landscape, positively changing the clinical
outcomes of several cancers such as melanoma and renal cell carcinoma , as well as malignancies
[48]
[49]
considered non-immunogenic such as non-small-cell lung cancer (NSCLC) [50,51] or mismatch-repair-
deficient colorectal cancer (CRC) . Immune checkpoint therapy targets regulatory pathways in T cells by
[52]
removing their inhibitory signals, thereby enabling tumor-reactive T cells to unleash an effective antitumor
response . An early study in antibiotic-treated mice showed altered GM that impaired both CpG-
[53]
oligonucleotide immunotherapy and platinum-based chemotherapy. On the other hand, the reduction of
tumor growth through the production of tumor necrosis factor alpha (TNFα) by myeloid cells and T cells
was shown in mice not receiving antibiotics. Indeed, antibiotic treatment impaired the production of TNFα
and other cytokines by immune cells including monocytes, macrophages, and dendritic cells, and reduced
tumor regression . Furthermore, the antitumor effect of anti-cytotoxic T-lymphocyte-associated protein 4
[42]
(anti-CTLA-4) antibodies was associated with the presence of distinct Bacteroides species that were able to
stimulate the T cell response against melanoma. Indeed, germ-free and antibiotic-treated mice did not
respond to anti-CTLA-4, while when they were gavaged with Bacteroides fragilis, a restoration of the
efficacy of the anticancer therapy was observed. The same anticancer outcomes were obtained only by
immunizing the same murine models with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-
specific T cells. In particular, B. fragilis was associated with Th1 immune responses in lymph nodes and