Alterations in the Gut Microbiota and Their Metabolites in Colorectal Cancer: Recent Progress and Future Prospects

Abstract

Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality worldwide. The etiology and pathogenesis of CRC remain unclear. A growing body of evidence suggests dysbiosis of gut bacteria can contribute to the occurrence and development of CRC by generating harmful metabolites and changing host physiological processes. Metabolomics, a systems biology method, will systematically study the changes in metabolites in the physiological processes of the body, eventually playing a significant role in the detection of metabolic biomarkers and improving disease diagnosis and treatment. Metabolomics, in particular, has been highly beneficial in tracking microbially derived metabolites, which has substantially advanced our comprehension of host-microbiota metabolic interactions in CRC. This paper has briefly compiled recent research progress of the alterations of intestinal flora and its metabolites associated with CRC and the application of association analysis of metabolomics and gut microbiome in the diagnosis, prevention, and treatment of CRC; furthermore, we discuss the prospects for the problems and development direction of this association analysis in the study of CRC. Gut microbiota and their metabolites influence the progression and causation of CRC, and the association analysis of metabolomics and gut microbiome will provide novel strategies for the prevention, diagnosis, and therapy of CRC.

Keywords: association analysis; colorectal cancer; gut microbiota; metabolites; metabolomics.

Figure 1

The schematic illustration of different cell processes triggered by SCFAs in CRC cells. Gut microbes catabolize unabsorbed dietary nutrients producing SCFAs. SCFAs can affect the inflammatory and immunological responses, colon cancer cell cycle arrest and apoptosis by influencing various receptors, signaling, apoptotic gene expression, which may be linked to the onset and progression of CRC. NFATc3, nuclear factor of activated T cells 3;CARD, proteins containing a caspase-associated recruitment domain; TNF, tumor necrosis factor; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Bcl-2, B cell lymphoma protein-2; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; IL-22, interleukin-22; IL-8, interleukin-8; IL-12, interleukin-12; IL-17, interleukin-17; IL-1β, interleukin-1β.

Figure 2

Secondary BAs promote CRC initiation and progression by inducing CRC-associated signaling. DCA and LCA are major secondary bile acids produced by gut bacteria through cholic acid metabolism, which can bind to host receptors, including nuclear hormone receptor FXR and G-protein-coupled receptor 1 (TGR5). This can increase the risk of CRC by triggering multiple cellular signals and genotoxicity, disrupting epithelial barrier integrity, driving inflammation immunological dysfunction. Multiple signaling pathways are involved in complex disease process. EGFR, epidermal growth factor receptor; FXR, farnesoid X receptor; Wnt, wingless-related integration site; ERK1/2, extracellular signal-regulated kinase 1/2; AA, arachidonic acid; PI3K/AKT, phosphatidylinositol-4,5-bisphosphate 3-kinase/serine-threonine kinase; EGF, epidermal growth factor; STAT3, signal transducer and activator of transcription 3.

Figure 3

The effects of Trp metabolites on CRC.As one of the most potent bioactive metabolites, bacterial Trp metabolites can activate the cytosolic ligand-activated transcription factor AhR and PXR, which can influence the release of cytokines and modulate gut immunological, inflammation, and barrier functions. ILC3, innate lymphoid cell 3; VEGFA, vascular endothelial growth factor A; MPO, mucosal myeloperoxidase; AMP, antimicrobial peptides; PTGS2, prostaglandin G/H synthase 2; PXR, pregnane X receptor; CYP1A1, cytochrome P450 1A1; AhR, aryl hydrocarbon receptor.