Potential Role of the Gut Microbiome In Colorectal Cancer Progression

Abstract

An increasing number of studies have revealed that the progression of colorectal cancer (CRC) is related to gut microbiome composition. Under normal conditions, the gut microbiome acts as a barrier to other pathogens or infections in the intestine and modulates inflammation by affecting the host immune system. These gut microbiota are not only related to the intestinal inflammation associated with tumorigenesis but also modulation of the anti-cancer immune response. Thus, they are associated with tumor progression and anti-cancer treatment efficacy. Studies have shown that the gut microbiota can be used as biomarkers to predict the effect of immunotherapy and improve the efficacy of immunotherapy in treating CRC through modulation. In this review, we discuss the role of the gut microbiome as revealed by recent studies of the growth and progression of CRC along with its synergistic effect with anti-cancer treatment modalities.

Keywords: chemotherapy; colorectal cancer; gut microbiota; immune checkpoint inhibitors; immunotherapy.

Figure 1

The relationship between the gut microbiome and sequential progression of colorectal carcinoma. Specific gut microorganisms induce chronic inflammation in the colorectal epithelium. For example, typhoid toxin or colibactin secreted by Salmonella or E. coli, respectively, leads to pro-inflammatory cytokine production and bacterial adherence. Chronic inflammation is one of the major causes of CRC and increased ROS with epithelial cell DNA damage also play a major role in cancer initiation by the gut microbiome. Some microorganisms like F. nucleatum and B. fragilis induce a tumor-favorable immune microenvironment by reducing CD3+ T cell density along with the recruitment and proliferation of CD4+CCR6+IL17A+ Th17 cells. Furthermore, bacterial components such as putative cell wall binding repeat 2 surface protein in P. anaerobius activate the NF-κB signaling pathway in CRC tumor cells and promote tumor cell proliferation. Colibactin-producing E. coli encodes enzymes responsible for HGF synthesis and induces senescence and tumor growth.

Figure 2

Effects of gut microbiome modulation on cancer treatment. Therapies which modulate the gut microbiome, including administration of probiotics or fecal microbiota transplantation, improve the efficacy of cancer treatment. Administration of antibiotics can reduce the efficacy of oxaliplatin and CpG oligodeoxynucleotides chemotherapeutic agents. The use of antibiotics increases pathogenic bacteria such as Escherichia shigella and Enterobacter, as well as reduces the anti-cancer effect of 5-FU. Radiation of the pelvic area causes dysbiosis and has the potential to affect the treatment modality of CRC. Furthermore, radiation-induced gut epithelial damage worsens the prognosis of CRC patients. These radiation side effects can be ameliorated through fecal microbiome transplantation as well as probiotics administration. The gut microbiota plays a role in modulating mucosal immunity in the colorectal region, acting to improve the efficacy of immunotherapy by enhancing the CD8+ T cell immune response or SCFA metabolite production.