Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer

Yachida, Shinichi; Mizutani, Sayaka; Shiroma, Hirotsugu; Shiba, Satoshi; Nakajima, Takeshi; Sakamoto, Taku; Watanabe, Hikaru; Masuda, Keigo; Nishimoto, Yuichiro; Kubo, Masaru; Hosoda, Fumie; Rokutan, Hirofumi; Matsumoto, Minori; Takamaru, Hiroyuki; Yamada, Masayoshi; Matsuda, Takahisa; Iwasaki, Motoki; Yamaji, Taiki; Yachida, Tatsuo; Soga, Tomoyoshi; Kurokawa, Ken; Toyoda, Atsushi; Ogura, Yoshitoshi; Hayashi, Tetsuya; Hatakeyama, Masanori; Nakagama, Hitoshi; Saito, Yutaka; Fukuda, Shinji; Shibata, Tatsuhiro; Yamada, Takuji

doi:10.1038/s41591-019-0458-7

Cited by 907 publications

(1,047 citation statements)

References 58 publications

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“…The abovementioned fecal branched‐chain amino acids, phenylalanine and pheC were identified as the best‐scoring markers to distinguish stage 0 cases from healthy controls in our study, suggesting their potential as non–invasive diagnostic markers for early stages of CRC. This relates to a diet‐based cancer prevention strategy in the sense that gut microbial fermentation of dietary amino acids may result in the production of detrimental metabolites such as phenylacetic acid, indole, p ‐cresol and N ‐nitroso compounds .…”

Section: Distinct Stage‐specific Phenotypes Of the Gut Microbiota Inmentioning

confidence: 56%

“…This suggests that F. nucleatum contributes in the very early stage of the adenoma-carcinoma sequence, which was in line with the abovementioned findings in mouse models and human cell lines. In contrast, 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, 28 which implies that these species might not cause carcinogenesis but are adapted to the cancerous environment. Second, we found that Atopobium parvulum and Actinomyces odontolyticus, whose relative abundances were higher than those of other CRC-associated bacteria, were significantly (P < .005) increased in multiple polypoid adenomas and/or in stage 0 but were not increased as significantly (P > .005) in more advanced stages.…”

Section: Ta B L E 1 Association Between Gut Bacteria and Colorectal Cmentioning

confidence: 95%

“…Bacteria related to colitis-associated CRC Enterotoxigenic Bacteroides fragilis 8 Adherent-invasive Escherichia coli 9 Genotoxic compound producing bacteria Pks + Escherichia coli strains (colibactin) 13 Clostridium hylemonae (deoxycholic acid) 12 Clostridium hiranonis (deoxycholic acid) 12 Bacteria related to non-colitis-associated CRC Fusobacterium nucleatum 10,11,[14][15][16]19,20 Parvimonas micra 20,26 Peptostreptococcus stomatis 19,20 Peptostreptococcus anaerobius 20,25 Atopobium parvulum 28 Actinomyces odontolyticus 28,30 factors in carcinogenesis, or whether they are a result of microbial adaptation to the tumor environment. Nevertheless, CRC-associated microbiota are currently globally accepted as CRC screening biomarkers that can be used as an alternative for the fecal occult blood test.…”

Section: Ta B L E 1 Association Between Gut Bacteria and Colorectal Cmentioning

confidence: 99%

“…We subjected these samples to whole-genome shotgun metagenomic sequencing and capillary electrophoresis time-of-flight mass spectrometry-based metabolomic studies to assess taxonomic and functional characteristics of the gut microbiota and metabolites ( Figure 1). 28 In addition, data on lifestyle were obtained from a detailed questionnaire (475 question items, 25 pages) that was developed on the basis of the questionnaire used in the Japan Public Health Center-based Prospective Study. 29 It includes questions on food frequency as well as known CRC risk factors (age, sex, smoking habits and alcohol consumption).…”

Section: Ta B L E 1 Association Between Gut Bacteria and Colorectal Cmentioning

confidence: 99%

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Significance of the gut microbiome in multistep colorectal carcinogenesis

2020

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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.

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Section: Distinct Stage‐specific Phenotypes Of the Gut Microbiota Inmentioning

confidence: 56%

Section: Ta B L E 1 Association Between Gut Bacteria and Colorectal Cmentioning

confidence: 95%

Section: Ta B L E 1 Association Between Gut Bacteria and Colorectal Cmentioning

confidence: 99%

Section: Ta B L E 1 Association Between Gut Bacteria and Colorectal Cmentioning

confidence: 99%

See 2 more Smart Citations

Significance of the gut microbiome in multistep colorectal carcinogenesis

2020

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“…Many scientists are now interested in studying the correlative relationships between microbes and metabolites (e.g., [1,2,3,4]). However, these kinds of analyses are complicated by the compositional (i.e., relative) nature of the data [5,6].…”

Section: Responsementioning

confidence: 99%

Another look at microbe–metabolite interactions: how scale invariant correlations can outperform a neural network

Quinn

Erb

2019

Preprint

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Many scientists are now interested in studying the correlative relationships between microbes and metabolites. However, these kinds of analyses are complicated by the compositional (i.e., relative) nature of the data. Recently, Morton et al. proposed a neural network architecture called mmvec to predict metabolite abundances from microbe presence. They introduce this method as a scale invariant solution to the integration of multi-omics compositional data, and claim that "mmvec is the only method robust to scale deviations". We do not doubt the utility of mmvec, but write in defense of simple linear statistics. In fact, when used correctly, correlation and proportionality can actually outperform the mmvec neural network.

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Parvimonas micra can translocate from the subgingival sulcus of the human oral cavity to colorectal adenocarcinoma

Conde‐Pérez,

Buetas,

Aja‐Macaya

et al. 2023

Molecular Oncology

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Oral and intestinal samples from a cohort of 93 colorectal cancer (CRC) patients and 30 healthy controls (non‐CRC) were collected for microbiome analysis. Saliva (28 non‐CRC and 94 CRC), feces (30 non‐CRC and 97 CRC), subgingival fluid (20 CRC) and tumor tissue samples (20 CRC) were used for 16S metabarcoding and/or RNA sequencing (RNAseq) approaches. A differential analysis of the abundance, performed with the ANCOM‐BC package, adjusting the p‐values by the Holm‐Bonferroni method, revealed that Parvimonas was significantly over‐represented in feces from CRC patients (p‐value <0.001) compared to healthy controls. A total of 11 Parvimonas micra isolates were obtained from the oral cavity and adenocarcinoma of CRC patients. Genome analysis identified a pair of isolates from the same patient that shared 99.2% identity, demonstrating that P. micra can translocate from the subgingival cavity to the gut. The data suggest that P. micra could migrate in a synergistic consortium with other periodontal bacteria. Metatranscriptomics confirmed that oral bacteria were more active in tumor than in non‐neoplastic tissues. We suggest that P. micra could be considered as a CRC biomarker detected in non‐invasive samples such as feces.

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Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer

Cited by 907 publications

References 58 publications

Significance of the gut microbiome in multistep colorectal carcinogenesis

Significance of the gut microbiome in multistep colorectal carcinogenesis

Another look at microbe–metabolite interactions: how scale invariant correlations can outperform a neural network

Parvimonas micra can translocate from the subgingival sulcus of the human oral cavity to colorectal adenocarcinoma

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