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.

Alteration of the abundance of <em>Parvimonas&nbsp;micra</em> in the gut along the adenoma‑carcinoma sequence

“…The present study identified a significant elevation of P. micra in CRC but not in CRA cases. Consistent with these findings, it has been shown that P. micra is predominantly enriched in stages I/II and III/IV, and its abundance is decreased after tumor resection, indicating that P. micra is not the cause of carcinogenesis but is adapted to the CRC microenvironment (50,51). Therefore, P. micra may be a passenger in the driver-passenger model.…”

“…A previous study demonstrated that APC Min/+ mice gavaged with P. micra exhibited a significantly higher tumor burden and tumor load, and cell proliferation was significantly higher in the colon tissues of P. micra gavaged germ-free mice compared with control mice (56). Furthermore, the tumor promoting effect of P. micra has been reported to be associated with altered immune responses and increased inflammation in the gut (50,56). These findings indicate that P. micra is primarily adapted to the CRC microenvironment and could contribute to a pro-tumoral inflammatory environment in patients susceptible to developing CRC.…”

Gut microbiota alterations are distinct for primary colorectal cancer and hepatocellular carcinoma

“…CRC-related microbiota could be classified to three distinct patterns (Mizutani et al, 2020). First, the abundances of gut microbes such as pro-inflammatory bacteria were elevated from stage 0 to more advanced stages, such as Fusobacterium nucleatum, Peptostreptococcus anaerobius, Peptostreptococcus stomatis, and Parvimonas micra., P. anaerobius, P. stomatis and P. micra were predominantly enriched in stage I/II and stage III/IV, and their abundances decreased after tumor resection, which implies that these species might not cause carcinogenesis but were adapted to the cancerous environment (Yachida et al, 2019).…”

Microbiome Analysis from Paired Mucosal and Fecal Samples of a Colorectal Cancer Biobank

“…The abundance of different microbiota also varies highly among healthy individuals depending on environmental conditions, genetics, the host’s immune system, diet as well as infections or use of antibiotics [ 9 , 10 ]. In colorectal cancer (CRC), there is an increasing evidence suggesting that the gut microbiota are associated with CRC development [ 11 , 12 ]. Gut microbiota show significant impact on processes involved in cellular DNA damage, DNA methylation, chromatin structure modulation and non-coding RNA expression [ 1 ].…”