The role of gut microbiota in cancer treatment: friend or foe?

Abstract

The gut microbiota has been implicated in cancer and shown to modulate anticancer drug efficacy. Altered gut microbiota is associated with resistance to chemo drugs or immune checkpoint inhibitors (ICIs), whereas supplementation of distinct bacterial species restores responses to the anticancer drugs. Accumulating evidence has revealed the potential of modulating the gut microbiota to enhance the efficacy of anticancer drugs. Regardless of the valuable findings by preclinical models and clinical data of patients with cancer, a more thorough understanding of the interactions of the microbiota with cancer therapy helps researchers identify novel strategy for cancer prevention, stratify patients for more effective treatment and reduce treatment complication. In this review, we discuss the scientific evidence on the role of gut microbiota in cancer treatment, and highlight the latest knowledge and technologies leveraged to target specific bacteria that contribute to tumourigenesis. First, we provide an overview of the role of the gut microbiota in cancer, establishing the links between bacteria, inflammation and cancer treatment. Second, we highlight the mechanisms used by distinct bacterial species to modulate cancer growth, immune responses, as well as the efficacy of chemotherapeutic drugs and ICIs. Third, we demonstrate various approaches to modulate the gut microbiota and their potential in translational research. Finally, we discuss the limitations of current microbiome research in the context of cancer treatment, ongoing efforts to overcome these challenges and future perspectives.

Keywords: cancer; intestinal microbiology.

Figure 1

Mechanisms used by gut bacteria to modulate anticancer drug efficacy. Bacterial species influence the efficacy of chemo drugs and immune checkpoint inhibitors via diverse mechanisms. Bacteria modulate the efficacy of 5-FU via bacterial vitamin B₆, B₉ and ribonucleotide metabolism. Inhibiting bacterial deoxynucleotide metabolism promotes the efficacy of 5-FU. Barnesiella intestinihominis and Enterococcus hirae play a critical role in the antitumour effect of another chemo drug, cyclophosphamide. Removing these bacterial species results in drug resistance to cyclophosphamide. Mechanistically, E. hirae translocates from the small intestine to secondary lymphoid organs and stimulates the production of pTh17 cells, whereas B. intestinihominis accumulates in the colon and promotes the infiltration of IFN-γ-producing γδT cells in cancer lesions on treatment with cyclophosphamide. In addition, Fusobacterium nucleatum acts via TLR4 and MYD88, induces a selective loss of miR-18a* and miR-4802, activates autophagy and thereby promotes chemoresistance in patients. Furthermore, the antitumour effect of anti-CTLA-4 treatment depends on Bacteroides species. Bacteroides fragilis colonises the mucosal layer, induces T helper 1 immune responses in the lymph nodes and promotes the maturation of intratumorous dendritic cells, mediating the anticancer activity of the immune checkpoint inhibitor. 5-FU, 5-fluorouracil; IFN-γ, interferon-gamma; pTh17 cells, pathogenic T helper 17 cells.

Figure 2

Preclinical mouse models and sequencing data of patients with cancer are valuable tools in microbiome research that contribute to the development of novel therapeutics for patients with cancer. Preclinical mouse models are valuable tools to dissect the mechanisms of defined bacteria in the absence of microbes (germ-free mice) or in the presence of limited number of microbes (antibiotic treatment). However, limitations, such as selection bias, prevent these preclinical models from fully recapitulating the interactions between the gut microbiota and cancer cells in humans. The antibiotic treatment may select for resistant bacteria or promote fungal outgrowth, confounding the result of the experiment. Other factors, including the housing environment, the diet and the genetic background of the mice, also influence the microbial communities residing in the mice and their interaction with tumour cells or anticancer drugs. To complement these preclinical models, cancer patients’ sequencing data are examined in terms of the host genome, metabolome and immune profile before and after anticancer treatment. Together, the mouse models and meta-analysis of human sequencing data provide insights into the relationship between the gut microbiota and cancer treatment. Modulating the gut microbiota by selectively targeting cancer-associated bacteria with phages, by administering probiotics or by performing FMT, may reshape the tumour microenvironment and the host immune responses, thereby augmenting the efficacy of anticancer drugs and improving the outcome of cancer patients. FMT, faecal microbiota transplant.