Role of the gut microbiota in anticancer therapy: from molecular mechanisms to clinical applications

Abstract

In the past period, due to the rapid development of next-generation sequencing technology, accumulating evidence has clarified the complex role of the human microbiota in the development of cancer and the therapeutic response. More importantly, available evidence seems to indicate that modulating the composition of the gut microbiota to improve the efficacy of anti-cancer drugs may be feasible. However, intricate complexities exist, and a deep and comprehensive understanding of how the human microbiota interacts with cancer is critical to realize its full potential in cancer treatment. The purpose of this review is to summarize the initial clues on molecular mechanisms regarding the mutual effects between the gut microbiota and cancer development, and to highlight the relationship between gut microbes and the efficacy of immunotherapy, chemotherapy, radiation therapy and cancer surgery, which may provide insights into the formulation of individualized therapeutic strategies for cancer management. In addition, the current and emerging microbial interventions for cancer therapy as well as their clinical applications are summarized. Although many challenges remain for now, the great importance and full potential of the gut microbiota cannot be overstated for the development of individualized anti-cancer strategies, and it is necessary to explore a holistic approach that incorporates microbial modulation therapy in cancer.

Fig. 1

Interactions between the gut microbiota and cancer development. The gut microbiota can interact with cancer through various patterns, one of which is contact-dependent interactions that occur locally at mucosal surface or within primary lymphoid organs including the bone marrow and the thymus (a), and secondary lymphoid organs including the GALT, lymph nodes and the spleen (b) or the TME (c). Another one is contact-independent interactions which present systematically via microbial metabolites and OMVs in circulation (c). Specifically, a Gut microbes can interact directly with the gastrointesinal tract mucosal surface, resulting in genotoxic effect, epithelial cell proliferation, loss of cellular polarity, intestinal metaplasia; the hematopoiesis of the thymic and bone marrow could be stimulated by microbiota via RIG-IFN-1 signaling especially after HSCT, thus making radio-protective effect in the radiotherapy. b Gut microbes and their metabolites or OMVs interact with the GALT, LN and spleen, through the T cells and dendritic cells regulations via various patterns, such as enhancement of the TH17 response, IFN production, antigen presentations and signaling of IFN-1, IL-12, TLR4. c Microbes both in the gut and tumor could exert influence on the TME, either with immunostimulatory effect via presenting microbial specific antigen to the T cells, or with immunosuppressive effect via regulating the balance of the Treg and TILs. Besides, microbial modulation of the TME exemplified are means by which microbiome-secreted metabolites, cargo-carrying OMVs, or may induce a complex array of immunomodulatory actions via circulation. Microbial secreted moieties can impact the TME innate immune response, by modulating attraction and activation of innate immune cells such as neutrophils, producing TNFα and ROS to combat tumorigenesis, and influence the adaptive immune response by co-stimulating T cells mentioned above. (HSCT hematopoietic stem cell transplant, DC dendritic cell, GALT gut-associated lymphoid tissues, LN lymph node, TLR4 Toll-like receptor 4, TME tumor microenvironment, CTL cytotoxic T lymphocyte, NK cell natural killer cell, OMVs outer membrane vesicles, SCFAs short-chain fatty acids, TIL tumor-infilrating lymphocyte, PRR pattern recognition receptor, MDSC myeloid-derived suppressor cells, ROS reactive oxygen species, TNF α tumor necrosis factor α)

Fig. 2

Mechanisms of microbial tumorigenesis and tumor suppression. a Mechanisms of microbes instigating tumorigenesis and tumor suppression in the gut: (1) mucosal dysregulations: For example, the virulence factor CagA secreted by H. pylori can inject into the mucosal cells via T4SS with the combination of CEACAM and HopQ, thereby promoting cell proliferation and improve the transformation rate of tumor cells. (2) aberrant signals transduction: For example, Fap2 extracted from F. nucleatum can mediate tumor progression via binding to the Gal-GalNAc, and OMVs from F. nucleatum can also stimulate colonic epithelial cells producing TNF and trigger IL-8 signaling; FadA, another pathogenic factor from F. nucleatum, can interact with E-cadherin on the epithelial cells and activate NF-κB pathway via Wnt/β-Catenin signaling, resulting in tumorigenesis. (3) DNA damage and induced genetics/epigenetics alteration: e.g. T3SS of Salmonella enterica can bind the effector protein AvrA and cyclomodulin-like protein typhoid toxin, promoting tumorigenesis genetically and epigenetically, through genotoxin-mediated mutagenesis. Specifically, AvrA promotes cell proliferation, differentiation and inhibits cell-cycle arrest via JAK/STAT, Wnt/β-catenin or acetyltransferase-targeted p53 pathway, collectively resulting in tumorigenesis. Escherichia coli can induce DNA damages via a secreted genotoxin, colibactin, which can break the DNA doublestrand and crosslinks. (4) immune suppression: For example, intratumoral microbes can reduce immunosurveillance effect via PRR ligation with larger proportions of Tregs and lower ratio of TILs, e.g. CD8 + T lymph cells, thus inducing tumor proliferation and metastasis. b Mechanisms of microbes instigating tumorigenesis and tumor suppression in the TME: (1) Immunity boosting: For example, bacterial metabolites can elevate IFN-γ-producing CD8 + T cells, enhance the therapeutic effect of ICIs in mouse models, and SCFAs from gut bacteria can stimulate the formation of mucus from goblet cells, inhibit NF-κB activation, elicit inflammation signal and produce IL-18, promote the secretion of sIgA from B cells, thus boosting the immunity. (2) Metabolite regulation in anti-cancer activity: For example, SCFAs, such as butyrate, from commensal bacteria can induce the differentiation of macrophage and increase the antibacterial activity of macrophage, partly through inhibition of HDAC3 activity, which plays a role in glycolysis and autophagy, thus regulating the tumorigenesis and tumor suppression. (CagA the cytotoxin-associated gene A, T4SS the type 4 secretion system, CEACAM carcinoembryonic antigen-related cell adhesion molecules, Hop Q outer membrane adhesion, OMVs outer membrane vesicles, TNF tumor necrosis factor, IL-8 interleukin-8, Treg regulatory T cell, TILs tumor infiltrating lymphocytes, TME tumor microenvironment, IFN- γ interferon γ, T3SS the type 3 secretion system, PRR pattern recognition receptor, ICIs immune checkpoint inhibitors, sIgA secretory IgA, SCFAs short-chain fatty acids, HDAC histone deacetylase)

Fig. 3

The mechanisms of microbiota impacting efficacy of cancer treatment. a Specifically, administration of Enterococcus and Barnesiella can restore the antitumor efficacy of cyclophosphamide-based chemotherapy through stimulating tumor-specific T cells and producing IFN-γ, and butyrate, a product of dietary fiber fermented by gut microbes, can increase the anticancer effects of oxaliplatin-based chemotherapy by regulating the function of CD8 + T cells in the TME through IL-12 signaling; b Lactobacillus rhamnosus was illustrated to stimulate the antitumor activity of PD-1 immunotherapy through cGAS-STING signal pathway, activating IFN-α, β signaling, and activating cytotoxic CD8 + T cells; SCFAs limit the antitumor effects of CTLA-4 blockade via alleviating Treg cells, and higher concentration of butyrate could decrease the anticancer activity of Ipilimumab by inhibiting the accumulation of related CD4 + T cells; c probiotics can protect gut mucosa from radiation injury through a TLR-2/COX-2-dependent manner, stimulating mesenchymal stem cells to the crypt. (FMT fecal microbiome transplantation, SCFAs short-chain fatty acids, IL interleukin, IFN- γ interferon γ, CTLA-4 cytotoxic T lymphocyte-associated antigen 4, Treg cell regulatory T cell, TLR Toll-like receptor, COX-2 cyclo-oxygenase-2)