Gut microbiota modulation: a novel strategy for prevention and treatment of colorectal cancer

Abstract

Research about the role of gut microbiome in colorectal cancer (CRC) is a newly emerging field of study. Gut microbiota modulation, with the aim to reverse established microbial dysbiosis, is a novel strategy for prevention and treatment of CRC. Different strategies including probiotics, prebiotics, postbiotics, antibiotics, and fecal microbiota transplantation (FMT) have been employed. Although these strategies show promising results, mechanistically by correcting microbiota composition, modulating innate immune system, enhancing gut barrier function, preventing pathogen colonization and exerting selective cytotoxicity against tumor cells, it should be noted that they are accompanied by risks and controversies that can potentially introduce clinical complications. During bench-to-bedside translation, evaluation of risk-and-benefit ratio, as well as patient selection, should be carefully performed. In view of the individualized host response to gut microbiome intervention, developing personalized microbiome therapy may be the key to successful clinical treatment.

Fig. 1. Putative mechanisms of actions of probiotics and their associated risks.

Probiotics may implicate in CRC prevention and treatment by functioning in three different mechanisms: (1) Colonization resistance. Probiotics inhibit colonization of pathogenic bacteria by releasing antimicrobial peptides, lowering luminal pH and/or directly interacting with pathogens (e.g., competing for nutrients and location, forming co-aggregates). (2) Modulating immunity. Probiotics can have distinct immunomodulatory effect to reduce colonic inflammation (e.g., activating DCs, reducing Th17, increasing Treg expression and shifting macrophage to M2 subtype) or enhance antitumor immunity (e.g., enhancing Th17 and reducing Treg expression at a systemic level, reducing tumor CXCR4 and MHC-1 expression), subject to the selected species and strains. (3) Enhanced gut barrier function. Probiotics increase mucin production and tight junction protein expression and promoted epithelial restitution. However, there has also been some safety concerns regarding probiotic use in cancer patients, including the risk of bacterial translocation and systemic invasion, as well as the potential transmission of resistant genes to resident microbiota and the rise of antimicrobial resistance. CXCR, CXC chemokine receptors 4; DCs, dendritic cells; MHC-1, major histocompatibility complex class I; Th17, T helper cell 17; Treg, T regulatory cell.

Fig. 2. Putative mechanisms of action of prebiotics and postbiotics.

Prebiotics function in the gut putatively via (1) stimulating probiotic growth, (2) selective fermentation by probiotics, (3) interacting with pathogens and preventing colonization and (4) being absorbed into intestine and exerting anti-inflammatory action, although the benefits of prebiotics may not be universal and subject to individual genetic background. On the other hand, postbiotics can (1) exert selective cytotoxicity against tumor cells and (2) protect intestinal epithelium by inhibiting apoptosis of normal epithelial cells and enhancing IgA secretion. IFN-γ, interferon-γ; IgA, immunoglobulin A; IL-10, interleukin-10.

Fig. 3. Putative mechanisms of action of antibiotics and fecal microbiota transplantation (FMT) and their associated safety concerns.

Gut dysbiosis often leads to the development of various diseases, therefore antibiotics and fecal microbiota transplantation are viable approaches to reverse dysbiosis and restore homeostasis. Antibiotics are effective in eradicating the pathogenic or harmful bacteria, but its non-selective antimicrobial actions may lead to another state of dysbiosis by killing the commensal microflora. It may also compromise the efficacy of cancer immunotherapy, which anticancer activity is modulated by commensal microbiota. On the other hand, FMT introduces a new bacterial community to the recipient, aiming to reverse the established dysbiosis. However, owing to the many unknown components presented in the donor’s samples, it also carries the risk of transmitting pathogens or disease-causing genes to the recipient.