The Intestinal Microbiota and Colorectal Cancer

Abstract

The intestinal microbiota, composed of a large population of microorganisms, is often considered a "forgotten organ" in human health and diseases. Increasing evidence indicates that dysbiosis of the intestinal microbiota is closely related to colorectal cancer (CRC). The roles for intestinal microorganisms that initiated and facilitated the CRC process are becoming increasingly clear. Hypothesis models have been proposed to illustrate the complex relationship between the intestinal microbiota and CRC. Recent studies have identified Streptococcus bovis, enterotoxigenic Bacteroides fragilis, Fusobacterium nucleatum, Enterococcus faecalis, Escherichia coli, and Peptostreptococcus anaerobius as CRC candidate pathogens. In this review, we summarized the mechanisms involved in microbiota-related colorectal carcinogenesis, including inflammation, pathogenic bacteria, and their virulence factors, genotoxins, oxidative stress, bacterial metabolites, and biofilm. We also described the clinical values of intestinal microbiota and novel strategies for preventing and treating CRC.

Keywords: biomarker; colorectal cancer; dietary intervention; inflammation; intestinal microbiota; metabolites.

Figure 1

Microbiota-associated mechanisms in colorectal carcinogenesis. The intestinal microbiota can regulate the initiation and progression of CRC. I. The infiltration of commensal bacteria or their products activates tumor-associated myeloid cells and induces tumor promoting inflammation. II. Pathogenic bacteria and their virulence factors adhere to IECs and promote tumorigenesis. III. Genotoxins produced by bacteria induce DNA damages in IECs and initiate CRC development. IV. Under the stimulation of chronic inflammation, inflammatory cells can produce ROS and RNS, which in turn induce DNA damage. V. Several bacterial metabolites, including secondary bile acids, H₂S and NOCs, can cause DNA damage, which promote CRC carcinogenesis. VI. Biofilm, microbial communities, promotes carcinogenesis through IL-6 and its downstream effector STAT3 activation. IEC, intestinal epithelial cell; H₂S, hydrogen sulfide; NOCs, N-nitroso compounds; CDT, cytolethal distending toxin; TT, typhoid toxin; MAMP, microbe-associated molecular pattern; LPS, lipopolysaccharide; PRR, pattern recognition receptor; TLR, Toll-like receptor; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor-κB; STAT3, signal transducer and activator of transcription 3; CAM, cell adhesin molecule; FadA, Fusobacterium adhesin A; TIGIT, T-cell immunoglobulin and ITIM domain; PCWBR2, putative cell wall binding repeat2; ROS, reactive oxygen species; RNS, reactive nitrogen species.