Characterization of commensal colibactin-producing Escherichia coli isolated from colorectal cancer patients

• Project/Area Number: 17K08841
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Bacteriology (including mycology)
• Research Institution: Nippon Veterinary and Life Science University
• Principal Investigator: Yoshikawa Yuko 日本獣医生命科学大学, 獣医学部, 講師 (00580523)
• Co-Investigator(Kenkyū-buntansha): 三好 規之 静岡県立大学, 食品栄養科学部, 准教授 (70438191)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: コリバクチン / 大腸菌 / 腸内細菌

Outline of Final Research Achievements

Colibactin is a genotoxin produced by a part of Escherichia coli is often isolated as an intestinal commensal. In this study, to clarify the relationship between commensal E. coli and colibactin production in Japanese colorectal adenocarcinoma, we investigated 729 E. coli strains isolated from tumor and its surrounding non-tumor regions of 34 Japanese colorectal adenocarcinoma patients. A total of 450 clb genes-positive (clb+) strains were isolated from 11 patients. The prevalence of clb+ strains in tumor regions was significantly higher than that in non-tumor regions. In addition, we demonstrated that hemolytic (hemolysin+) clb+ strains were dominant in tumor regions, and these bacteria accelerated the production of N-myristoyl-D-asparagine (N-myr-Asn), a by-product of colibactin biosynthesis. These results suggested that E. coli, equipped with both hemolysin and colibactin, possess an advantage in colorectal colonization and subsequent carcinogenesis.

Academic Significance and Societal Importance of the Research Achievements

ここ数年、大腸がんの罹患率は部位別の上位を占め、さらに他のがんと比較すると増加が著しい。腫瘍部位におけるコリバクチン産生菌の優占化および大腸がんや炎症性腸疾患の患者におけるコリバクチン産生菌の高い検出率から、大腸におけるコリバクチンの産生増加が、大腸がんの発生に関連するリスクファクターの1つであることが推測される。それゆえ、本研究の成果はコリバクチン産生菌の大腸粘膜上皮への局所的な集積を防ぐ腸内環境の是正方法やコリバクチン産生の制御法の開発へとつながり、さらにはコリバクチンを精度の高い大腸がんのリスクマーカーとして確立できれば、優れたがんの一次予防戦略と成り得る。

Research Products

• [Journal Article] Characterization of Colibactin-Producing <i>Escherichia coli</i> Isolated from Japanese Patients with Colorectal Cancer (2020)
  • Author(s): Yoshikawa Yuko、Tsunematsu Yuta、Matsuzaki Nobuo、Hirayama Yuichiro、Higashiguchi Fumi、Sato Michio、Iwashita Yuji、Miyoshi Noriyuki、Mutoh Michihiro、Ishikawa Hideki、Sugimura Haruhiko、Wakabayashi Keiji、Watanabe Kenji
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 73 Issue: 6 Pages: 437-442
  • DOI: 10.7883/yoken.JJID.2020.066
  • NAID: 130007942237
  • ISSN: 1344-6304, 1884-2836
  • Year and Date: 2020-11-30
  • Peer Reviewed
• [Journal Article] Unique response characteristics in persistent strains of Listeria monocytogenes exposed to low pH. (2020)
  • Author(s): Yoshitsugu Ochiai, Yuko Yoshikawa, Mariko Mochizuki, Takashi Takano and Fukiko Ueda.
  • Journal Title: Food Microbiology Volume: 86 Pages: 103312-103312
  • DOI: 10.1016/j.fm.2019.103312
  • Peer Reviewed
• [Journal Article] Intracellular proliferation of Anaplasma phagocytophilum is promoted via modulation of endoplasmic reticulum stress signaling in host cells (2020)
  • Author(s): Yoshikawa Y, Sugimoto K, Ochiai Y, Ohashi N.
  • Journal Title: Microbiol Immunol. Volume: 64 Issue: 4 Pages: 70-279
  • DOI: 10.1111/1348-0421.12770
  • Peer Reviewed
• [Journal Article] Genotyping of a gene cluster for production of colibactin and in vitro genotoxicity analysis of Escherichia coli strains obtained from the Japan Collection of Microorganisms (2020)
  • Author(s): Kawanishi Masanobu、Shimohara Chiaki、Oda Yoshimitsu、Hisatomi Yuuta、Tsunematsu Yuta、Sato Michio、Hirayama Yuichiro、Miyoshi Noriyuki、Iwashita Yuji、Yoshikawa Yuko、Sugimura Haruhiko、Mutoh Michihiro、Ishikawa Hideki、Wakabayashi Keiji、Yagi Takashi、Watanabe Kenji
  • Journal Title: Genes and Environment Volume: 42 Issue: 1 Pages: 12-17
  • DOI: 10.1186/s41021-020-00149-z
  • Peer Reviewed / Open Access
• [Journal Article] Elevated levels of proinflammatory volatile metabolites in feces of high fat diet fed KK-Ay mice (2020)
  • Author(s): Uchikawa Misaki、Kato Mai、Nagata Akika、Sanada Shunsuke、Yoshikawa Yuto、Tsunematsu Yuta、Sato Michio、Suzuki Takuji、Hashidume Tsutomu、Watanabe Kenji、Yoshikawa Yuko、Miyoshi Noriyuki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 5681-5681
  • DOI: 10.1038/s41598-020-62541-7
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal microbial metabolite stercobilin involvement in the chronic inflammation of ob/ob mice (2020)
  • Author(s): Sanada Shunsuke、Suzuki Takuji、Nagata Akika、Hashidume Tsutomu、Yoshikawa Yuko、Miyoshi Noriyuki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 6479-6479
  • DOI: 10.1038/s41598-020-63627-y
  • Peer Reviewed / Open Access
• [Journal Article] Wheat bran intake enhances the secretion of bacteria-binding IgA in a lumen of the intestinal tract by incrementing short chain fatty acid production through modulation of gut microbiota. (2020)
  • Author(s): Konosuke Matsuzaki, Katsuki Iwai, Yuko Yoshikawa, Yuko Shimamura, Noriyuki Miyoshi, Shigeru Hiramoto, Kenichi Asada, Ryuuta Fukutomi, Hongru Su and Norio Ohashi
  • Journal Title: Natural Product Communications Volume: 15 Issue: 4 Pages: 1-11
  • DOI: 10.1177/1934578x20917791
  • Peer Reviewed
• [Journal Article] Genetic variation of mitochondrial DNA in <i>Phalacrocorax carbo</i> in Japan (2020)
  • Author(s): Yoshitsugu Ochiai, Yuko Yoshikawa, Takashi Takano, Makoto Mori, Ryo Hondo, Mariko Mochizuki, Fukiko Ueda.
  • Journal Title: Journal of Veterinary Medical Science Volume: 82 Issue: 6 Pages: 735-739
  • DOI: 10.1292/jvms.19-0360
  • NAID: 130007855271
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed
• [Journal Article] Activity-Based Probe for Screening of High-Colibactin Producers from Clinical Samples (2019)
  • Author(s): Hirayama Yuichiro、Tsunematsu Yuta、Yoshikawa Yuko、Tamafune Ryota、Matsuzaki Nobuo、Iwashita Yuji、Ohnishi Ippei、Tanioka Fumihiko、Sato Michio、Miyoshi Noriyuki、Mutoh Michihiro、Ishikawa Hideki、Sugimura Haruhiko、Wakabayashi Keiji、Watanabe Kenji
  • Journal Title: Organic Letters Volume: 21 Issue: 12 Pages: 4490-4494
  • DOI: 10.1021/acs.orglett.9b01345
  • Peer Reviewed
• [Journal Article] <i>In vitro</i> genotoxicity analyses of colibactin-producing <i>E. coli</i> isolated from a Japanese colorectal cancer patient (2019)
  • Author(s): Kawanishi Masanobu、Hisatomi Yuuta、Oda Yoshimitsu、Shimohara Chiaki、Tsunematsu Yuta、Sato Michio、Hirayama Yuichiro、Miyoshi Noriyuki、Iwashita Yuji、Yoshikawa Yuko、Sugimura Haruhiko、Mutoh Michihiro、Ishikawa Hideki、Wakabayashi Keiji、Yagi Takashi、Watanabe Kenji
  • Journal Title: The Journal of Toxicological Sciences Volume: 44 Issue: 12 Pages: 871-876
  • DOI: 10.2131/jts.44.871
  • NAID: 130007759775
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access
• [Journal Article] Sequence-Based Characterization of <i>Listeria monocytogenes</i> Strains Isolated from Domestic Retail Meat in the Tokyo Metropolitan Area of Japan (2018)
  • Author(s): Yoshikawa, Y., Ochiai, Y., Mochizuki, M., Takano, T., Hondo, R., and Ueda, F.
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 71 Issue: 5 Pages: 373-377
  • DOI: 10.7883/yoken.JJID.2017.582
  • NAID: 130007485647
  • ISSN: 1344-6304, 1884-2836
  • Year and Date: 2018-09-30
  • Peer Reviewed
• [Journal Article] Green soybean extract ameliorates dextran sodium sulfate-induced colitis. (2018)
  • Author(s): Yoshikawa, Y., Murakami, T., Katayanagi, Y., Yasui, K., Ohgo, Y., Imai, S., and Ohashi, N.
  • Journal Title: Natural Product Communications Volume: 13 Pages: 209-212
  • Peer Reviewed
• [Journal Article] Molecular mechanisms of Streptococcus pneumoniae-targeted autophagy via pneumolysin, Golgi-resident Rab41, and Nedd4-1-mediated K63-linked ubiquitination (2018)
  • Author(s): Ogawa M, Matsuda R, Takada N, Tomokiyo M, Yamamoto S, Shizukusihi S, Yamaji T, Yoshikawa Y, Yoshida M, Tanida I, Koike M, Murai M, Morita H, Takeyama H, Ryo A, Guan JL, Yamamoto M, Inoue JI, Yanagawa T, Fukuda M, Kawabe H, Ohnishi M
  • Journal Title: Cellular Microbiology Volume: e12846 Issue: 8
  • DOI: 10.1111/cmi.12846
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of sanyaku and its constituent diosgenin on the fasted and postprandial hypertriacylglycerolemia in high fat diet-fed KK-Ay mice. (2018)
  • Author(s): Hashidume, T., Sasaki, K., Hirata, J., Kato, M., Yoshikawa, Y., Iwasaki, Y., Arai, H., Miura, S., and Miyoshi, N.
  • Journal Title: Journal of Agricultural and Food Chemistry Volume: 66 Issue: 38 Pages: 9968-9975
  • DOI: 10.1021/acs.jafc.8b03040
  • Peer Reviewed
• [Journal Article] Tomato saponin supplementation ameliorates the development of experimental arthritis by regulating inflammatory responses (2018)
  • Author(s): Yoshikawa Y, Katayanagi Y, Kamiya M, Yamamoto Y, Fukutomi R, Imai S, Miyoshi N, Ohashi N.
  • Journal Title: J. Funct. Foods Volume: 49 Pages: 458-464
  • DOI: 10.1016/j.jff.2018.09.009
  • Peer Reviewed
• [Journal Article] Effects of Short-Term Intake of Wheat Bran with Different Particle Sizes on the Murine Intestinal Environment (2017)
  • Author(s): Iwai, K., Yoshikawa, Y., Miyoshi, N., Fukutomi, R., Asada, K., and Ohashi, N.
  • Journal Title: Food Science and Technology Research Volume: 23 Issue: 5 Pages: 733-742
  • DOI: 10.3136/fstr.23.733
  • NAID: 130006183136
  • ISSN: 1344-6606, 1881-3984
  • Peer Reviewed
• [Journal Article] Sequential transition of the injury phenotype, temperature-dependent survival and transcriptional response in Listeria monocytogenes following lethal H2O2 exposure. (2017)
  • Author(s): Ochiai, Y., Yamada, F., Yoshikawa, Y., Mochizuki, M., Takano, T., Hondo, R., and Ueda, F.
  • Journal Title: International Journal of Food Microbiology Volume: 259 Pages: 52-58
  • DOI: 10.1016/j.ijfoodmicro.2017.08.001
  • Peer Reviewed
• [Presentation] 大腸がん患者から分離した遺伝毒性物質コリバクチン合成遺伝子陽性大腸菌の解析 (2019)
  • Author(s): 吉川悠子, 平山裕一郎, 松崎信生, 東口ふみ, 恒松雄太, 佐藤道大, 三好規之, 岩下雄二, 椙村春彦, 若林敬二, 武藤倫弘, 石川秀樹, 渡辺賢二
  • Organizer: 第26回がん予防学会学術大会
• [Presentation] NASH‐肝発がんモデルマウスの糞便中揮発性化合物による発がんバイオマーカー探索 (2019)
  • Author(s): 加藤麻衣, 橋詰力, 庄司豊, 庄司（加藤）久美子, 五十嵐美樹, 早川清雄, 吉川悠子, 三好規之
  • Organizer: 第26回がん予防学会学術大会
• [Presentation] 大腸発がんリスク因子コリバクチンの生産性を制御する要因の解明 (2019)
  • Author(s): 恒松雄太, 吉川悠子, 三好規之, 武藤倫弘, 山地太樹, 張萌琳, 岩崎基, 松田尚久, 細見晃司, 國澤純, 若林敬二, 石川秀樹, 渡辺賢二
  • Organizer: 第26回がん予防学会学術大会
• [Presentation] 遺伝毒性物質コリバクチン生産菌の高感度多検体検出法の確立 (2019)
  • Author(s): 佐藤道大, 平山裕一郎, 恒松雄太, 東口ふみ, 吉川悠子, 三好規之, 岩下雄二, 椙村春彦, 若林敬二, 武藤倫弘, 石川秀樹, 渡辺賢二
  • Organizer: 第26回がん予防学会学術大会
• [Presentation] 鶏肉からのCampylobacter属菌およびListeria属菌の分離状況(2) (2019)
  • Author(s): 小林清美, 吉川悠子, 高野貴士, 落合由嗣, 望月眞理子, 植田富貴子
  • Organizer: 第162回日本獣医学会学術集会
• [Presentation] Analysis of fecal gaseous metabolites in NASH-hepatocellular carcinoma model mice. (2019)
  • Author(s): Kato Mai, Hashidume Tsutomu, Shoji Yutaka, Shoji Kumiko, Igarashi Miki, Hayakawa Sumio, Yoshikawa Yuko, Miyoshi Noriyuki.
  • Organizer: ICoFF2019
  • Int'l Joint Research
• [Presentation] 大腸がん患者から分離された遺伝毒性物質コリバクチン陽性菌の解析 (2018)
  • Author(s): 吉川悠子, 恒松雄太, 松崎信生, 平山裕一郎, 佐藤道大, 三好規之, 岩下雄二, 椙村春彦, 若林敬二, 渡辺賢二
  • Organizer: 第91回日本細菌学会総会
• [Presentation] 高脂肪食を摂取したNASH‐肝発がんモデルマウス糞便中揮発性化合物の分析 (2018)
  • Author(s): 加藤麻衣, 橋詰力, 庄司豊, 庄司（加藤）久美子, 五十嵐美樹, 早川清雄, 吉川悠子, 三好規之
  • Organizer: 第72回日本栄養・食糧学会大会
• [Presentation] 大腸がんリスク因子物質コリバクチンの生産菌検出に関する化学的研究 (2018)
  • Author(s): 平山裕一郎, 松崎信生, 玉舟亮太, 恒松雄太, 佐藤道大, 吉川悠子, 三好規之, 岩下雄二, 椙村春彦,若林敬二, 武藤倫弘, 石川秀樹, 渡辺賢二
  • Organizer: 第25回がん予防学会学術大会
• [Presentation] 鶏肉からのCampylobacter属菌およびListeria属菌の分離状況 (2018)
  • Author(s): 小林清美, 吉川悠子, 高野貴士, 落合由嗣, 望月眞理子, 植田富貴子
  • Organizer: 第161 回日本獣医学会学術集会
• [Presentation] Lipid A biosynthesis in E. coli cultured in metal-depletion (2018)
  • Author(s): Ohashi, S., Hashidume, T., Ishizuka, N., Hayashi, H., Kawarasaki, Y., Watanabe, K, Yoshikawa, Y., Miyoshi, N.
  • Organizer: The 4th International Conference on Pharma-Food
• [Presentation] Assay for proinflammatory activity of structurally modified lipid A. (2018)
  • Author(s): Ohashi, S., Hashidume, T., Ishizuka, N., Hayashi, H., Kawarasaki, Y., Watanabe, K, Yoshikawa, Y., Miyoshi, N.
  • Organizer: 第23回 静岡健康・長寿学術フォーラム
• [Presentation] 腸内細菌叢を起源とする遺伝毒性物質コリバクチンの科学分析手法の確立と日本人コホートにおける発がんとの関連性の解析 (2017)
  • Author(s): 恒松雄太、平山裕一郎、桝谷貴洋、松崎信生、佐藤道大、吉川悠子、三好規之、若林敬二、武藤倫弘、村上晴香、宮地元彦、石川秀樹、渡辺賢二
  • Organizer: がん予防学術大会2017
• [Presentation] 食品から分離されたListeria monocytogenesのストレス抵抗性に関する解析 (2017)
  • Author(s): 落合由嗣、吉川悠子、山田文也、高野貴士、望月眞理子、本藤良、植田富貴子
  • Organizer: 第160回日本獣医学会学術集会