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

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

Research output: Contribution to journalArticlepeer-review

570 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)968-976
Number of pages9
JournalNature medicine
Issue number6
Publication statusPublished - 2019 Jun 1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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