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Page 6 of 12 Procaccianti et al. Microbiome Res Rep 2023;2:24 https://dx.doi.org/10.20517/mrr.2023.23

Table 1. Clinical trials registered in the last two years on ClinicalTrials.gov (as accessed in March 2023) involving the use of
Bifidobacterium spp. as adjuvant therapy in cancer patients. Search terms included “cancer” or “tumor” in combination with “
Bifidobacterium”
Title Status Results Condition Intervention Location URL
Safety and Efficacy of Recruiting Not Advanced Bifidobacterium China https://clinicaltrials.gov/ct2/show/NCT05620004
Bifidobacterium Therapy in available Hepatocellular bifidum oral
Patients With Advanced Carcinoma product
Liver Cancer Receiving
Immunotherapy
Clinical Study on BIFICO Completed Not Hepatocellular BIFICO ( China https://clinicaltrials.gov/ct2/show/NCT05178524
Accelerating Postoperative available Carcinoma Bifidobacterium
Liver Function Recovery in -based
Patients With product)
Hepatocellular Carcinoma
Lactobacillus Recruiting Not Non-Small Cell Bifidobacterium China https://clinicaltrials.gov/ct2/show/NCT05094167
Bifidobacterium V9 available Lung Cancer and
(Kex02) Improving the Lactobacillus;
Efficacy of Carilizumab Placebo
Combined With Platinum
in Non-small Cell Lung
Cancer Patients
Effect of Live Combined Unknown Not Oral mucositis Lactobacillus, China https://clinicaltrials.gov/ct2/show/NCT03112837
Bifidobacterium, status available in Bifidobacterium
Lactobacillus and Nasopharyngeal and
Enterococcus Capsules on Carcinoma Enterococcus
Oral Mucositis in
NasopharyngealCarcinoma
Patients Receiving
Radiotherapy

On the other hand, evidence is also accumulating on a not entirely favorable role of Bifidobacterium in the
response to immunochemotherapy. For example, Bifidobacterium were found to be overabundant in the
GM of platinum-resistant patients treated for epithelial ovarian cancer . As speculated by the authors, the
[70]
lactate produced by these microbes as part of their metabolism could fuel the “Warburg effect” (i.e., the
production of lactate by aerobic glycolysis) [71,72] . Increased lactate production is frequently observed in
tumor cells, where it promotes angiogenesis, tumor growth, inflammation, metastasis, epithelial-
mesenchymal transition and immune evasion. The hypothesis put forward by the authors is therefore that
Bifidobacterium, and potentially other lactic acid bacteria, are capable of interfering with the lactate cycle,
increasing its local and systemic bioavailability and thus influencing tumor progression, as well as the
efficacy of chemotherapy. While fascinating, it should be noted that these speculations are based on the
detection of increased proportions of Bifidobacterium and other potential lactate producers (and predicted
lactate production pathways) while decreased proportions of lactate utilizers in platinum-resistant vs.
platinum-sensitive patients, without direct measurement of lactate levels (and its isoforms). In this regard,
the lactate levels typically produced in the intestine are much lower than those obtained at the tumor site by
[72]
the Warburg effect , further underlining the need to verify the proposed link. Furthermore, it cannot be
ruled out that GM alterations in potential lactate producers/utilizers are only a side effect of chemotherapy,
in combination with other host factors, with no direct role in treatment response. However, there is
previous evidence that similarly demonstrated an increase in lactic acid bacteria, including Bifidobacterium,
in patients with gastrointestinal cancer, and suggested a role for them in influencing tumor development,
[73]
also through exogenous lactate supply . Once again, these are purely associative observations, which
makes proof of concept mandatory, especially in extra-intestinal cancers.

In support of the latter speculations, it should be mentioned that Bifidobacterium has a known anti-
inflammatory role, mediated by the production of SCFAs and induction of Treg cells and IL-10, so it is not
entirely unreasonable to doubt its ability to promote antitumor immune responses. Perhaps the