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

doi:10.1038/s41591-019-0458-7

. 2019 Jun;25(6):968-976.

doi: 10.1038/s41591-019-0458-7. Epub 2019 Jun 6.

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

Shinichi Yachida^#^{1

2}, Sayaka Mizutani^#³, Hirotsugu Shiroma³, Satoshi Shiba⁴, Takeshi Nakajima⁵, Taku Sakamoto⁵, Hikaru Watanabe³, Keigo Masuda³, Yuichiro Nishimoto³, Masaru Kubo³, Fumie Hosoda⁴, Hirofumi Rokutan⁴, Minori Matsumoto⁵, Hiroyuki Takamaru⁵, Masayoshi Yamada⁵, Takahisa Matsuda⁵, Motoki Iwasaki⁶, Taiki Yamaji⁶, Tatsuo Yachida⁷, Tomoyoshi Soga⁸, Ken Kurokawa⁹, Atsushi Toyoda¹⁰, Yoshitoshi Ogura¹¹, Tetsuya Hayashi¹¹, Masanori Hatakeyama¹², Hitoshi Nakagama¹³, Yutaka Saito⁵, Shinji Fukuda^{8

14

15

16}, Tatsuhiro Shibata^{4

17}, Takuji Yamada^{18

19}

Affiliations

¹ Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan. syachida@cgi.med.osaka-u.ac.jp.
² Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. syachida@cgi.med.osaka-u.ac.jp.
³ School of Life Science and Technology, Tokyo Institute of Technology, Tokyo, Japan.
⁴ Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
⁵ Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan.
⁶ Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
⁷ Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
⁸ Institute for Advanced Biosciences, Keio University, Yamagata, Japan.
⁹ Genome Evolution Laboratory, National Institute of Genetics, Shizuoka, Japan.
¹⁰ Comparative Genomics Laboratory, National Institute of Genetics, Shizuoka, Japan.
¹¹ Department of Bacteriology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹² Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹³ National Cancer Center, Tokyo, Japan.
¹⁴ Intestinal Microbiota Project, Kanagawa Institute of Industrial Science and Technology, Kanagawa, Japan.
¹⁵ Transborder Medical Research Center, University of Tsukuba, Ibaraki, Japan.
¹⁶ PRESTO, Japan Science and Technology Agency, Saitama, Japan.
¹⁷ Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹⁸ School of Life Science and Technology, Tokyo Institute of Technology, Tokyo, Japan. takuji@bio.titech.ac.jp.
¹⁹ PRESTO, Japan Science and Technology Agency, Saitama, Japan. takuji@bio.titech.ac.jp.

^# Contributed equally.

PMID: 31171880
DOI: 10.1038/s41591-019-0458-7

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

Shinichi Yachida et al. Nat Med. 2019 Jun.

. 2019 Jun;25(6):968-976.

doi: 10.1038/s41591-019-0458-7. Epub 2019 Jun 6.

Authors

Affiliations

¹ Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan. syachida@cgi.med.osaka-u.ac.jp.
² Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. syachida@cgi.med.osaka-u.ac.jp.
³ School of Life Science and Technology, Tokyo Institute of Technology, Tokyo, Japan.
⁴ Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
⁵ Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan.
⁶ Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
⁷ Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
⁸ Institute for Advanced Biosciences, Keio University, Yamagata, Japan.
⁹ Genome Evolution Laboratory, National Institute of Genetics, Shizuoka, Japan.
¹⁰ Comparative Genomics Laboratory, National Institute of Genetics, Shizuoka, Japan.
¹¹ Department of Bacteriology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹² Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹³ National Cancer Center, Tokyo, Japan.
¹⁴ Intestinal Microbiota Project, Kanagawa Institute of Industrial Science and Technology, Kanagawa, Japan.
¹⁵ Transborder Medical Research Center, University of Tsukuba, Ibaraki, Japan.
¹⁶ PRESTO, Japan Science and Technology Agency, Saitama, Japan.
¹⁷ Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹⁸ School of Life Science and Technology, Tokyo Institute of Technology, Tokyo, Japan. takuji@bio.titech.ac.jp.
¹⁹ PRESTO, Japan Science and Technology Agency, Saitama, Japan. takuji@bio.titech.ac.jp.

^# Contributed equally.

PMID: 31171880
DOI: 10.1038/s41591-019-0458-7

Abstract

In most cases of sporadic colorectal cancers, tumorigenesis is a multistep process, involving genomic alterations in parallel with morphologic changes. In addition, accumulating evidence suggests that the human gut microbiome is linked to the development of colorectal cancer. Here we performed fecal metagenomic and metabolomic studies on samples from a large cohort of 616 participants who underwent colonoscopy to assess taxonomic and functional characteristics of gut microbiota and metabolites. Microbiome and metabolome shifts were apparent in cases of multiple polypoid adenomas and intramucosal carcinomas, in addition to more advanced lesions. We found two distinct patterns of microbiome elevations. First, the relative abundance of Fusobacterium nucleatum spp. was significantly (P < 0.005) elevated continuously from intramucosal carcinoma to more advanced stages. Second, Atopobium parvulum and Actinomyces odontolyticus, which co-occurred in intramucosal carcinomas, were significantly (P < 0.005) increased only in multiple polypoid adenomas and/or intramucosal carcinomas. Metabolome analyses showed that branched-chain amino acids and phenylalanine were significantly (P < 0.005) increased in intramucosal carcinomas and bile acids, including deoxycholate, were significantly (P < 0.005) elevated in multiple polypoid adenomas and/or intramucosal carcinomas. We identified metagenomic and metabolomic markers to discriminate cases of intramucosal carcinoma from the healthy controls. Our large-cohort multi-omics data indicate that shifts in the microbiome and metabolome occur from the very early stages of the development of colorectal cancer, which is of possible etiological and diagnostic importance.

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References

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1. Zeller, G. et al. Potential of fecal microbiota for early-stage detection of colorectal cancer. Mol. Syst. Biol. 10, 766 (2014). - DOI

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[1] Brenner, H., Kloor, M. & Pox, C. P. Colorectal cancer. Lancet 383, 1490–1502 (2014). - DOI

[2] Brenner, H., Kloor, M. & Pox, C. P. Colorectal cancer. Lancet 383, 1490–1502 (2014). - DOI

[3] Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990). - DOI

[4] Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990). - DOI

[5] Jones, S. et al. Comparative lesion sequencing provides insights into tumor evolution. Proc. Natl Acad. Sci. USA 105, 4283–4288 (2008). - DOI

[6] Jones, S. et al. Comparative lesion sequencing provides insights into tumor evolution. Proc. Natl Acad. Sci. USA 105, 4283–4288 (2008). - DOI

[7] Ashktorab, H., Kupfer, S. S., Brim, H. & Carethers, J. M. Racial disparity in gastrointestinal cancer risk. Gastroenterology 153, 910–923 (2017). - DOI

[8] Ashktorab, H., Kupfer, S. S., Brim, H. & Carethers, J. M. Racial disparity in gastrointestinal cancer risk. Gastroenterology 153, 910–923 (2017). - DOI

[9] Zeller, G. et al. Potential of fecal microbiota for early-stage detection of colorectal cancer. Mol. Syst. Biol. 10, 766 (2014). - DOI

[10] Zeller, G. et al. Potential of fecal microbiota for early-stage detection of colorectal cancer. Mol. Syst. Biol. 10, 766 (2014). - DOI

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

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

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