From promotion to management: the wide impact of bacteria on cancer and its treatment

Abstract

In humans, the intestine is the major reservoir of microbes. Although the intestinal microbial community exists in a state of homeostasis called eubiosis, environmental and genetics factors can lead to microbial perturbation or dysbiosis, a state associated with various pathologies including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Dysbiotic microbiota is thought to contribute to the initiation and progression of CRC. At the opposite end of the spectrum, two recently published studies in Science reveal that the microbiota is essential for chemotherapeutic drug efficacy, suggesting a beneficial microbial function in cancer management. The dichotomy between the beneficial and detrimental roles of the microbiota during cancer initiation, progression, and treatment emphasize the interwoven relationship between bacteria and cancer. Moreover, these findings suggest that the microbiota could be considered as a therapeutic target, not only at the level of cancer prevention, but also during management, i.e. by enhancing the efficacy of chemotherapeutics.

Keywords: cancer; chemotherapy; dysbiosis; intestinal microbiota; therapeutic efficacy.

Figure 1

At eubiosis stage, the intestinal epithelium contains a rich and diverse biota that promotes the barrier function. Short-chain fatty acids (SCFAs), such as butyrate and propionate promote the differentiation of regulatory T-cells (Treg), thereby down-regulating inflammatory responses from effector T-cells (T_H17 and T_H1) cells, and maintaining homeostasis. Events that disrupt microbial community lead to a state of dysbiosis and loss of homeostasis. Microbial dysbiosis favors the production of genotoxins and metabolites associated with carcinogenesis. Microbes such as F. Nucleatum and E. coli are associated with colorectal cancer. Dysregulated immune responses cause inflammation and epithelial disruption, which further enhance microbial translocation, exacerbating immune activation and promoting carcinogenesis.

Figure 2

Microbes promote the therapeutic efficacy of chemotherapeutic drugs, reducing the size of extra-intestinal tumors. A: Cyclophosphamide (CTX) damages the epithelial layer, resulting in the translocation of Gram + bacteria to secondary lymphoid tissues such as the spleen, with subsequent differentiation of naïve T cells into pathogenic anti-tumor T_H17 and T_H1 cells. B: The chemotherapeutic efficacy of the anticancer regimen (CpG-ODN/anti-IL10 antibodies) is increased by the gut microbiota, in particular microbes belonging to the genera Alistipes and Ruminococcus. These microbes ‘prime’ myeloid cell responses resulting in a potent TNFα-mediated response. Oxaliplatin causes apoptosis of tumor cells through the generation of radical oxygen species.

Figure 3

Intestinal microbial composition modulates tumor development. Dysbiotic intestinal microbiome containing tumor-promoting microbes fosters cancer development (e.g. CRC). On the other hand, the microbiota is essential for the therapeutic efficacy of chemotherapeutic drugs, either by ‘priming’ the anti-tumor immune responses (CHX, CpG-ODN) or by facilitating anti-tumor toxicity (oxaliplatin).