The microbiome and cancer

Abstract

Microbiota and host form a complex 'super-organism' in which symbiotic relationships confer benefits to the host in many key aspects of life. However, defects in the regulatory circuits of the host that control bacterial sensing and homeostasis, or alterations of the microbiome, through environmental changes (infection, diet or lifestyle), may disturb this symbiotic relationship and promote disease. Increasing evidence indicates a key role for the bacterial microbiota in carcinogenesis. In this Opinion article, we discuss links between the bacterial microbiota and cancer, with a particular focus on immune responses, dysbiosis, genotoxicity, metabolism and strategies to target the microbiome for cancer prevention.

Figure 1. Mechanisms controlling host–microbiota interactions and associated failures implicated in cancer development

A state of homeostasis and symbiotic relationships is maintained by the separation of microbial entities from the host through a multi-level barrier, by a eubiotic microbiome that actively suppresses pathobionts and that maintains a symbiotic relationship with the host, and by a state of low inflammation in the host. Perturbation of this balance leads to chain reactions that ultimately result in a cancer-promoting state with a failing barrier, inflammation and dysbiosis. This state includes qualitative and sometimes quantitative changes in the microbiota; failure of the barrier either physically (for example, at the level of tight junctions or at the mucous layer), or at the level of antibacterial defence systems — either those of epithelial cells or those of cells from the gut-associated lymphoid tissue (GALT); and increased inflammatory responses, which are often mediated by pattern recognition receptors (PRRs) and downstream cytokines that promote epithelial cell proliferation and survival. DCA, deoxycholic acid; EREG, epiregulin; IgA, immunoglobulin A; IL-6, interleukin-6; MAMP, microorganism-associated molecular pattern; NF-κB, nuclear factor-κB; T_H17, T helper 17; TNF, tumour necrosis factor.

Figure 2. Mechanisms by which the bacterial microbiome modulates carcinogenesis

The bacterial microbiome promotes carcinogenesis through several mechanisms. a | Changes in the microbiome and host defences may favour increased bacterial translocation, leading to increased inflammation, which is mediated by microorganism-associated molecular patterns (MAMPs) that activate Toll-like receptors (TLRs) in several cell types, including macrophages, myofibroblasts, epithelial cells and tumour cells. These effects may occur locally or through long-distance effects in other organs. b | Genotoxic effects are mediated by bacterial genotoxins — such as colibactin and cytolethal distending toxin (CDT) — that, after being delivered to the nucleus of host cells, actively induce DNA damage in organs that are in direct contact with the microbiome, such as the gastrointestinal tract. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) released from inflammatory cells such as macrophages, as well as hydrogen sulphide (H₂S) from the bacterial microbiota, may also be genotoxic. c | Metabolic actions of the microbiome may result in the activation of genotoxins such as acetaldehyde, dietary nitrosamine and other carcinogens, in the metabolism of hormones such as oestrogen and testosterone, in the metabolism of bile acids and in alterations of energy harvest. The microbiota also mediates tumour suppressive effects (shown in green) through inactivation of carcinogens, through the generation of short-chain fatty acids such as butyrate and through the biological activation of cancer-preventing phytochemicals. Many of these tumorigenic and tumour-suppressive mediators exert both local and longdistance effects. AREG, amphiregulin; DCA, deoxycholic acid; EREG, epiregulin; IL, interleukin; NF-κB, nuclear factor-κB; NLR, NOD-like receptor; STAT3, signal transducer and activator of transcription 3; T_H17, T helper 17; TNF, tumour necrosis factor.

Figure 3. Targeting the bacterial microbiota for therapeutic modulation of carcinogenesis

On the basis of the known contribution of the bacterial microbiota in experimental carcinogenesis, the approaches shown are conceivable for the prevention of human carcinogenesis.