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

被引:887
作者
Yachida, Shinichi [1 ,2 ]
Mizutani, Sayaka [3 ]
Shiroma, Hirotsugu [3 ]
Shiba, Satoshi [2 ]
Nakajima, Takeshi [4 ]
Sakamoto, Taku [4 ]
Watanabe, Hikaru [3 ]
Masuda, Keigo [3 ]
Nishimoto, Yuichiro [3 ]
Kubo, Masaru [3 ]
Hosoda, Fumie [2 ]
Rokutan, Hirofumi [2 ]
Matsumoto, Minori [4 ]
Takamaru, Hiroyuki [4 ]
Yamada, Masayoshi [4 ]
Matsuda, Takahisa [4 ]
Iwasaki, Motoki [5 ]
Yamaji, Taiki [5 ]
Yachida, Tatsuo [6 ]
Soga, Tomoyoshi [7 ]
Kurokawa, Ken [8 ]
Toyoda, Atsushi [1 ,9 ]
Ogura, Yoshitoshi [10 ]
Hayashi, Tetsuya [10 ]
Hatakeyama, Masanori [11 ]
Nakagama, Hitoshi [12 ]
Saito, Yutaka [4 ]
Fukuda, Shinji [7 ,13 ,14 ,15 ]
Shibata, Tatsuhiro [2 ,16 ]
Yamada, Takuji [3 ,15 ]
机构
[1] Osaka Univ, Grad Sch Med, Dept Canc Genome Informat, Osaka, Japan
[2] Natl Canc Ctr, Res Inst, Div Canc Genom, Tokyo, Japan
[3] Tokyo Inst Technol, Sch Life Sci & Technol, Tokyo, Japan
[4] Natl Canc Ctr, Endoscopy Div, Tokyo, Japan
[5] Natl Canc Ctr, Epidemiol & Prevent Grp, Ctr Publ Hlth Sci, Tokyo, Japan
[6] Kagawa Univ, Dept Gastroenterol & Neurol, Fac Med, Takamatsu, Kagawa, Japan
[7] Keio Univ, Inst Adv Biosci, Yamagata, Japan
[8] Natl Inst Genet, Genome Evolut Lab, Shizuoka, Japan
[9] Natl Inst Genet, Comparat Genom Lab, Shizuoka, Japan
[10] Kyushu Univ, Dept Bacteriol, Fac Med Sci, Fukuoka, Fukuoka, Japan
[11] Univ Tokyo, Grad Sch Med, Dept Microbiol, Tokyo, Japan
[12] Natl Canc Ctr, Tokyo, Japan
[13] Kanagawa Inst Ind Sci & Technol, Intestinal Microbiota Project, Ebina, Kanagawa, Japan
[14] Univ Tsukuba, Med Res Ctr, Ibaraki, Japan
[15] Japan Sci & Technol Agcy, PRESTO, Saitama, Japan
[16] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Mol Med, Tokyo, Japan
基金
日本学术振兴会; 日本科学技术振兴机构;
关键词
FUSOBACTERIUM-NUCLEATUM; MOLECULAR-FEATURES; CATABOLIC PATHWAY; FERMENTATION; METABOLITES; BACTERIA; ACIDS; 16S;
D O I
10.1038/s41591-019-0458-7
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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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页码:968 / +
页数:27
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