Significance of the gut microbiome in multistep colorectal carcinogenesis

Abstract

Colorectal cancer (CRC) is highly prevalent worldwide. In 2018, there were over 1.8 million new cases. Most sporadic CRC develop from polypoid adenomas and are preceded by intramucosal carcinoma (stage 0), which can progress into more malignant forms. This developmental process is known as the adenoma-carcinoma sequence. Early detection and endoscopic removal are crucial for CRC management. Accumulating evidence suggests that the gut microbiota is associated with CRC development in humans. Comprehensive characterization of this microbiota is of great importance to assess its potential as a diagnostic marker in the very early stages of CRC. In this review, we summarized recent studies on CRC-associated bacteria and their carcinogenic mechanisms in animal models, human cell lines and human cohorts. High-throughput technologies have facilitated the identification of CRC-associated bacteria in human samples. We have presented our metagenome and metabolome studies on fecal samples collected from a large Japanese cohort that revealed stage-specific phenotypes of the microbiota in CRC. Furthermore, we have discussed the potential carcinogenic mechanisms of the gut microbiota, from which we can infer whether changes in the gut microbiota are a cause or effect in the multi-step process of CRC carcinogenesis.

Keywords: adenoma-carcinoma sequence; colorectal cancer; gut microbiome; metabolome; metagenome.

Figure 1

Metagenomic and metabolomic data from our Japanese cohort study. (Upper panel) Relative abundances of the top 15 genera for 576 subjects in the healthy control (N = 251), multiple polypoid adenomas (MP) (N = 67), stage 0 (N = 73), stage I/II (N = 111) and stage III/IV (N = 74) groups. Bifidobacterium and Megamonas are highly abundant, a notable characteristic of the Japanese cohort. Whereas Bifidobacterium is prevalent in the entire population, Megamonas abundance strongly differs among individuals. (Lower panel) Percentage concentrations of top 15 metabolites for 372 subjects in the healthy control (N = 149), MP (N = 45), stage 0 (N = 30), stage I/II (N = 80) and stage III/IV (N = 68) groups

Figure 2

Three types of colorectal cancer (CRC)‐associated taxonomic signatures in our Japanese cohort study. Relative abundances of known CRC‐related species (A), species that are newly associated to multiple polypoid adenomas and stage 0 (B), and species that are depleted in CRC (C), in healthy control, multiple polypoid adenomas, stage 0, stage I/II and stage III/IV groups. The boxes represent the 25th‐75th percentiles; the median is indicated by a black horizontal line, and maximum and minimum values within 1.5 times the interquartile range are indicated by a vertical line. +++, elevation at P < .005; ++, elevation at P < .01; +, elevation at P < .05; −−−, depletion at P < .005; −−, depletion at P < .01; −, depletion at P < .05 (one‐sided Mann‐Whitney U test). P < .005 was considered statistically significant

Figure 3

Stage‐specific changes of bile acids and amino acids in our Japanese cohort study. Fecal concentrations of bile acids, branched‐chain amino acids, and aromatic amino acids in patients in healthy control, multiple polypoid adenomas (MP), stage 0 (S0), stage I/II (SI/II) and stage III/IV (SIII/IV) groups. The boxes represent the 25th‐75th percentiles, the median is indicated by a black horizontal line, and maximum and minimum values within 1.5 times the interquartile range are indicated by a vertical line. +++, elevation at P < .005; ++, elevation at P < .01; +, elevation at P < .05; −−−, depletion at P < .005; −−, depletion at P < .01; −, depletion at P < .05 (one‐sided Mann‐Whitney U test)

Figure 4

Dietary fiber and calcium intakes in the Japanese cohort study. Dietary intake data were collected from a food frequency questionnaire. Total fiber and calcium intake (g/d) were adjusted to 1 kcal of energy. Data from outliers (energy < 600 kcal or > 3500 kcal) were excluded. The boxes represent the 25th‐75th percentiles, the median is indicated by a black horizontal line, and maximum and minimum values within 1.5 times the interquartile range are indicated by a vertical line. P‐values are obtained from one‐sided Mann‐Whitney U test with the alternative hypothesis that dietary intake in each of the stages is lower than in healthy controls. H, healthy controls; MP, multiple polypoid adenomas; S0, stage 0; SI/II, stage I/II; SIII/IV, stage III/IV

Figure 5

Distinct colorectal cancer (CRC) stage‐specific changes in the gut microbiota. (Upper panel) Bacterial relative abundances in our Japanese cohort study. Values are the median of all samples in each of the five participant groups: healthy control (N = 251), multiple polypoid adenomas (N = 67), stage 0 (N = 73), stage I/II (N = 111) and stage III/IV (N = 74). Three patterns of elevations in abundance can be distinguished. First, Fusobacterium nucleatum abundance starts to increase at stage 0 and continues to increase with cancer progression. Second, Atopobium parvulum and Actinomyces odontolyticus are significantly increased in cases with multiple polypoid adenomas and/or stage 0 but no longer increase in more advanced stages. Third, Peptostreptococcus anaerobius, Peptostreptococcus stomatis,and Parvimonas micra increase in later stages, stage I/II and stage III/IV. (Lower panels) Representative microscopic images of H&E‐stained colorectal tissue sections from each of the participant groups