Gut Microbiome in Colorectal Cancer: Clinical Diagnosis and Treatment

Abstract

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers and the leading cause of cancer-associated deaths. Epidemiological studies have shown that both genetic and environmental risk factors contribute to the development of CRC. Several metagenomic studies of CRC have identified gut dysbiosis as a fundamental risk factor in the evolution of colorectal malignancy. Although enormous efforts and substantial progresses have been made in understanding the relationship between human gut microbiome and CRC, the precise mechanisms involved remain elusive. Recent data have shown a direct causative role of the gut microbiome in DNA damage, inflammation, and drug resistance in CRC, suggesting that modulation of gut microbiome could act as a powerful tool in CRC prevention and therapy. Here, we provide an overview of the relationship between gut microbiome and CRC, and explore relevant mechanisms of colorectal tumorigenesis. We next highlight the potential of bacterial species as clinical biomarkers, as well as their roles in therapeutic response. Factors limiting the clinical translation of gut microbiome and strategies for resolving current challenges are further discussed.

Keywords: Chemotherapy; Colorectal cancer; Diagnostic biomarker; Gut microbiome; Immunotherapy.

Figure 1

Enriched bacterial species in CRC Several bacterial species are significantly enriched in tissue biopsies or fecal samples of patients with CRC. These bacteria can potentially serve as CRC biomarkers. For example, combining the detection of fecal Fusobacterium nucleam and Clostridium symbiosum with FIT has improved the diagnostic performance of advanced adenoma and CRC , . The sensitivity of FIT for advanced adenoma can also be enhanced by detecting the enrichment of a group of genera, including Fusobacterium, Peptostreptococcus, Porphyromonas, Prevotella, Parvimonas, Bacteroides, and Gemella. Well-studied CRC-enriched bacteria are highlighted in bold and shadow. CRC, colorectal cancer; FIT, fecal immunochemical test.

Figure 2

Influence of the gut microbiome on CRC chemotherapy and immunotherapy Gut commercial microbes mediate the response of cancer cells to the chemotherapeutic drug oxaliplatin by modulating the functions of myeloid-derived cells in the tumor microenvironment . Barneslella intestinihominis and Enterococcus hirae can be translocated to lymphoid tissues, facilitating immunomodulatory effects induced by another chemotherapeutic drug, cyclophosphamide . Bifidobacterium pseudolongum produces the metabolite inosine to enhance the anti-CTLA-4 immunotherapeutic response through activating A_2AR expressed in antitumor T cells . A_2AR, type 2a adenosine receptor; APC, antigen-presenting cell; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; IFNγ, interferon-gamma; IL-12, interleukin-12; MYD88, myeloid differentiation primary response 88; pTH17, pathogenic T helper 17 cell; ROS, reactive oxygen species; Tc1, type 1 CD8⁺ T cell; TH1, T helper 1 cell; TLR4, toll-like receptor 4.