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Page 4 of 12 Procaccianti et al. Microbiome Res Rep 2023;2:24 https://dx.doi.org/10.20517/mrr.2023.23

Figure 1. Bifidobacterium and its controversial role in the response to anticancer immunochemotherapy. Bifidobacterium spp. have been
associated with response to immunochemotherapy through stimulation and activation of effector T lymphocytes and dendritic cells. On
the other hand, Bifidobacterium spp. have been associated with induction of Treg cells, stimulation of anti-inflammatory cytokines, and
general immunosuppressive effects (also mediated by short-chain fatty acids – SCFAs). Furthermore, the ability of Bifidobacterium to
produce lactate suggests a hypothetical link with the “Warburg effect”, known to promote tumor growth, thus potentially liming the
effect of immunochemotherapy. The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a
Creative Commons Attribution 3.0 unported license and images from Flaticon resources.

dendritic cell maturation in the tumor environment, thereby reverting CTLA-4 blockade. Similar results
were obtained in melanoma patients in whom anti-CTLA-4 efficacy was associated with T cell responses
mediated by an overabundance of B. fragilis or Bacteroides thetaiotaomicron . Fecal microbial
[48]
transplantation from humans to murine models further confirmed that anti-CTLA-4 treatment favored the
outgrowth of B. fragilis with all the anticancer properties discussed above. More recently, GM analysis of
metastatic melanoma patients receiving ipilimumab, a CTLA-4-targeted immune checkpoint inhibitor,
revealed that elevated levels of Faecalibacterium and other members of the phylum Firmicutes were
associated with not only longer survival but also reduced occurrence of ipilimumab-induced colitis .
[54]
Similarly, programmed cell death protein 1 (PD-1) is one of the inhibitory receptors that downregulate
effector functions and suppress the immune response leading to non-activation of the immune cascade
against tumors. Immunotherapy against PD-1 allowed to achieve tumor regression in a subset of
cancers [55-59] . As for GM, studies in renal and lung cancers showed that non-responders were characterized
by reduced levels of Akkermansia muciniphila, which promoted the recruitment of activated T lymphocytes
into the tumor microenvironment via the IL-12 pathway . A recent study confirmed the relevance of
[47]
[60]
Akkermansia as a prognostic factor for NSCLC patients treated with immune checkpoint inhibitors .
Specifically, the authors found that baseline relative abundance of Akkermansia was linked to therapeutic