Gut dysbiosis: a potential link between increased cancer risk in ageing and inflammaging

Abstract

Cancer incidence substantially increases with ageing in both men and women, although the reason for this increase is unknown. In this Series paper, we propose that age-associated changes in gut commensal microbes, otherwise known as the microbiota, facilitate cancer development and growth by compromising immune fitness. Ageing is associated with a reduction in the beneficial commensal microbes, which control the expansion of pathogenic commensals and maintain the integrity of the intestinal barrier through the production of mucus and lipid metabolites, such as short-chain fatty acids. Expansion of gut dysbiosis and leakage of microbial products contributes to the chronic proinflammatory state (inflammaging), which negatively affects the immune system and impairs the removal of mutant and senescent cells, thereby enabling tumour outgrowth. Studies in animal models and the importance of commensals in cancer immunotherapy suggest that this status can be reversible. Thus, interventions that alter the composition of the gut microbiota might reduce inflammaging and rejuvenate immune functions to provide anticancer benefits in frail elderly people.

Figure 1. Inflammaging and age-associated gut dysbiosis

Through their control of inflammation, commensals activate monocytes involved in homoeostasis and immune surveillance. Ageing changes the composition of gut commensals. For example, the number of beneficial bacteria are reduced, whereas pathogenic bacteria are increased. This change promotes a chain of inflammatory events that lead to chronic inflammation (inflammaging). SCFA=short-chain fatty acid. MAMPs=microbe-associated molecular patterns. PAMPS=pathogen-associated molecular patterns. +=present. CCR2=C-C chemokine receptor type 2.

Figure 2. Ageing gut dysbiosis and cancer

In young hosts, beneficial gut microbiota activate immune cells to mediate proper cancer immune surveillance to eliminate malignant and impaired cells via senescence, phagocytosis, and cytolytic killing. However, gut dysbiosis in ageing induces chronic inflammation, which reduces immune fitness and provides a selective benefit to oncogene-expressing and malignant cells. Gut dysbiosis impairs the removal of senescent and dormant tumour cells by phagocytes, impairs the induction of tumour-specific cytolytic CD8 T cells by plasmacytoid dendritic cells, and enhances the expansion of myeloid-derived suppressive cells and regulatory T cells in cancer. By contrast, it can also slow growth of some tumours in ageing; for example, by utilising activated innate B1a cells (4BL cells) that induce antitumor cytolytic granzyme-positive CD8 T cells. Treg=Regulatory T cell.