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Procaccianti et al. Microbiome Res Rep 2023;2:24 https://dx.doi.org/10.20517/mrr.2023.23 Page 7 of 12

discriminating factor, as the studies commented above suggest, is the use of immune vs. chemotherapy
protocols. In the context of immunotherapy, we hypothesize that Bifidobacterium-induced Treg cells in the
intestine might migrate into the tumor microenvironment and promote tumor cell evasion mechanisms
from immunosurveillance. In this regard, in a very elegant and recent study in murine models, Fidelle et al.
revealed that enterotropic T cells can actually relocate to distant tumors and impair the therapeutic efficacy
[74]
of immune checkpoint inhibitors . Notably, such a relocation was favored by gut dysbiosis-induced
downregulation of the expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) on
intestinal endothelial cells, which usually helps retain an immunosuppressive set of T cells (Treg17 cells)
within the gut, through interaction with integrin 47. Disruption of MAdCAM-1-47 interaction triggered the
migration of Treg17 cells from the ileal lamina propria and gut-associated lymphoid tissues to distant
tumors and tumor-draining lymph nodes, where they impaired the therapeutic efficacy of immune
checkpoint inhibitors by producing immunosuppressive molecules such as IL-10, CD39 and CD73.
Moreover, the tumor microenvironment was found to be associated with metabolic reprogramming of
tumor-infiltrating Treg cells, which increases their reliance on fatty acid (instead of glucose) metabolism,
[75]
further contributing to the Warburg effect . However, the process of Treg cell migration to tumor sites and
the interaction of migrated immune cells with cancer cells (including factors driving their metabolic
behavior) are highly complex processes not yet fully understood. More evidence is needed to better
elucidate the role of gut-primed Tregs in cancer immunosurveillance and whether/how Bifidobacterium (or
other GM components) is involved in this intricate picture.

GUT MICROBIOME-BASED ANTICANCER INTERVENTION STRATEGIES INVOLVING
BIFIDOBACTERIUM SPP
The results of clinical and preclinical studies investigating the functional roles of Bifidobacterium spp. in the
cancer setting have so far been sadly inconclusive. However, the use of Bifidobacterium as a probiotic, alone
or in combination with Lactobacillus spp., has led to numerous benefits in multiple pathological contexts .
[76]
With specific regard to cancer, the intake of Bifidobacterium spp. conferred protection against CRC
[77]
[78]
development in mice and improved immune function in CRC patients . Furthermore, Bifidobacterium
mitigated the secondary effects of surgery and chemotherapy in patients with CRC, as well as in those
undergoing colectomy or resection of liver metastases [79,80] . In particular, B. breve reduced post-
chemotherapy GM dysbiosis and limited the development of infections in a pediatric cohort . In contrast,
[81]
another study focused on head and neck cancer patients treated with a cocktail of Bifidobacterium spp. and
Lactobacillus spp. showed no improvement in patients’ clinical outcomes (i.e., inflammatory markers and
[82]
gut permeability) . However, it should be mentioned that these conflicting results may be partly explained
by interindividual variations in GM and host genomes. Indeed, several studies confirmed that the intestinal
colonization and functionality of probiotics are strongly influenced by the individual GM, the host gene
expression profile, and other exogenous factors [83-85] .

Notwithstanding the above, a number of clinical trials have been planned (some of which are still ongoing)
to examine the therapeutic potential of Bifidobacterium interventions in cancer patients. A list of clinical
studies registered in the previous two years is shown in Table 1. In an ongoing interventional randomized
study of 30 participants with advanced liver cancer receiving immunotherapy, Xie et al. are profiling the
GM of patients receiving or not a cocktail of lactic acid bacteria, including Bifidobacterium spp.
(NCT05620004). Another interventional randomized clinical trial was designed to evaluate the impact of
oral administration of Lactobacillus and Bifidobacterium on 46 participants with NSCLC on the efficacy of
immunochemotherapy (NCT05094167). Other ongoing studies are investigating the role of Bifidobacterium
in improving the conditions of patients before and after cancer removal surgery, by mitigating therapy-
related side effects [86,87] . Furthermore, in a randomized controlled clinical trial of 180 patients with