Gut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion

Shintaro Okumura; Yusuke Konishi; Megumi Narukawa; Yuki Sugiura; Shin Yoshimoto; Yuriko Arai; Shintaro Sato; Yasuo Yoshida; Shunya Tsuji; Ken Uemura; Masahiro Wakita; Tatsuyuki Matsudaira; Tomonori Matsumoto; Shimpei Kawamoto; Akiko Takahashi; Yoshiro Itatani; Hiroaki Miki; Manabu Takamatsu; Kazutaka Obama; Kengo Takeuchi; Makoto Suematsu; Naoko Ohtani; Yosuke Fukunaga; Masashi Ueno; Yoshiharu Sakai; Satoshi Nagayama; Eiji Hara

doi:10.1038/s41467-021-25965-x

Gut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion

Shintaro Okumura, Yusuke Konishi, Megumi Narukawa, Yuki Sugiura, Shin Yoshimoto, Yuriko Arai, Shintaro Sato, Yasuo Yoshida, Shunya Tsuji, Ken Uemura, Masahiro Wakita, Tatsuyuki Matsudaira, Tomonori Matsumoto, Shimpei Kawamoto, Akiko Takahashi, Yoshiro Itatani, Hiroaki Miki, Manabu Takamatsu, Kazutaka Obama, Kengo TakeuchiMakoto Suematsu, Naoko Ohtani, Yosuke Fukunaga, Masashi Ueno, Yoshiharu Sakai, Satoshi Nagayama, Eiji Hara

Department of Biochemistry

Research output: Contribution to journal › Article › peer-review

56 Citations (Scopus)

Abstract

Emerging evidence is revealing that alterations in gut microbiota are associated with colorectal cancer (CRC). However, very little is currently known about whether and how gut microbiota alterations are causally associated with CRC development. Here we show that 12 faecal bacterial taxa are enriched in CRC patients in two independent cohort studies. Among them, 2 Porphyromonas species are capable of inducing cellular senescence, an oncogenic stress response, through the secretion of the bacterial metabolite, butyrate. Notably, the invasion of these bacteria is observed in the CRC tissues, coinciding with the elevation of butyrate levels and signs of senescence-associated inflammatory phenotypes. Moreover, although the administration of these bacteria into Apc^Δ14/+ mice accelerate the onset of colorectal tumours, this is not the case when bacterial butyrate-synthesis genes are disrupted. These results suggest a causal relationship between Porphyromonas species overgrowth and colorectal tumourigenesis which may be due to butyrate-induced senescence.

Original language	English
Article number	5674
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25965-x
Publication status	Published - 2021 Dec 1

ASJC Scopus subject areas

General
Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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Okumura, S., Konishi, Y., Narukawa, M., Sugiura, Y., Yoshimoto, S., Arai, Y., Sato, S., Yoshida, Y., Tsuji, S., Uemura, K., Wakita, M., Matsudaira, T., Matsumoto, T., Kawamoto, S., Takahashi, A., Itatani, Y., Miki, H., Takamatsu, M., Obama, K., ... Hara, E. (2021). Gut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion. Nature communications, 12(1), [5674]. https://doi.org/10.1038/s41467-021-25965-x

Okumura, S, Konishi, Y, Narukawa, M, Sugiura, Y, Yoshimoto, S, Arai, Y, Sato, S, Yoshida, Y, Tsuji, S, Uemura, K, Wakita, M, Matsudaira, T, Matsumoto, T, Kawamoto, S, Takahashi, A, Itatani, Y, Miki, H, Takamatsu, M, Obama, K, Takeuchi, K, Suematsu, M, Ohtani, N, Fukunaga, Y, Ueno, M, Sakai, Y, Nagayama, S & Hara, E 2021, 'Gut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion', Nature communications, vol. 12, no. 1, 5674. https://doi.org/10.1038/s41467-021-25965-x

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title = "Gut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion",

abstract = "Emerging evidence is revealing that alterations in gut microbiota are associated with colorectal cancer (CRC). However, very little is currently known about whether and how gut microbiota alterations are causally associated with CRC development. Here we show that 12 faecal bacterial taxa are enriched in CRC patients in two independent cohort studies. Among them, 2 Porphyromonas species are capable of inducing cellular senescence, an oncogenic stress response, through the secretion of the bacterial metabolite, butyrate. Notably, the invasion of these bacteria is observed in the CRC tissues, coinciding with the elevation of butyrate levels and signs of senescence-associated inflammatory phenotypes. Moreover, although the administration of these bacteria into ApcΔ14/+ mice accelerate the onset of colorectal tumours, this is not the case when bacterial butyrate-synthesis genes are disrupted. These results suggest a causal relationship between Porphyromonas species overgrowth and colorectal tumourigenesis which may be due to butyrate-induced senescence.",

author = "Shintaro Okumura and Yusuke Konishi and Megumi Narukawa and Yuki Sugiura and Shin Yoshimoto and Yuriko Arai and Shintaro Sato and Yasuo Yoshida and Shunya Tsuji and Ken Uemura and Masahiro Wakita and Tatsuyuki Matsudaira and Tomonori Matsumoto and Shimpei Kawamoto and Akiko Takahashi and Yoshiro Itatani and Hiroaki Miki and Manabu Takamatsu and Kazutaka Obama and Kengo Takeuchi and Makoto Suematsu and Naoko Ohtani and Yosuke Fukunaga and Masashi Ueno and Yoshiharu Sakai and Satoshi Nagayama and Eiji Hara",

note = "Funding Information: We thank Dr. Kenya Honda (Keio University) for valuable advice for gut bacterial culture and Dr. Daisuke Okuzaki (Osaka University) for performing RNA-seq analysis. We also thank Ms. Satoko Otomi, Ms. Shizuka Murata, Mr. Masanori Tanaka, Dr. Tomohiro Tsuchida and Dr. Shoichi Saito (JFCR) for collecting human specimens, Ms. Yuko Wakabayashi, Ms. Tamae Kondo, Ms. Masae Suzuki (Osaka University), Ms. Satoko Baba and Dr. Ryoji Yao (JFCR) for technical supports throughout this study. We are grateful to Dr. Toshiki Mukai, Dr. Tomohiro Yamaguchi, Dr. Toshiya Nagasaki, Dr. Takashi Akiyoshi, Dr. Tsuyoshi Konishi (JFCR) and members of Hara{\textquoteright}s laboratory for helpful discussion during the preparation of this manuscript. This work was supported in part by grants from the Japan Agency of Medical Research and Development (AMED) under grant numbers 19gm501000h0003 and 19cm0106401h0004, from the Japan Science and Technology Agency (JST) under grant number JPMJMS2022 and from the Japan Society for the Promotion of Science (JSPS) under grant numbers 19K16612, 18K15065, 16H06276 (AdAMS), 26250028 and 18K15188. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

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doi = "10.1038/s41467-021-25965-x",

language = "English",

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T1 - Gut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion

AU - Okumura, Shintaro

AU - Konishi, Yusuke

AU - Narukawa, Megumi

AU - Sugiura, Yuki

AU - Yoshimoto, Shin

AU - Arai, Yuriko

AU - Sato, Shintaro

AU - Yoshida, Yasuo

AU - Tsuji, Shunya

AU - Uemura, Ken

AU - Wakita, Masahiro

AU - Matsudaira, Tatsuyuki

AU - Matsumoto, Tomonori

AU - Kawamoto, Shimpei

AU - Takahashi, Akiko

AU - Itatani, Yoshiro

AU - Miki, Hiroaki

AU - Takamatsu, Manabu

AU - Obama, Kazutaka

AU - Takeuchi, Kengo

AU - Suematsu, Makoto

AU - Ohtani, Naoko

AU - Fukunaga, Yosuke

AU - Ueno, Masashi

AU - Sakai, Yoshiharu

AU - Nagayama, Satoshi

AU - Hara, Eiji

N1 - Funding Information: We thank Dr. Kenya Honda (Keio University) for valuable advice for gut bacterial culture and Dr. Daisuke Okuzaki (Osaka University) for performing RNA-seq analysis. We also thank Ms. Satoko Otomi, Ms. Shizuka Murata, Mr. Masanori Tanaka, Dr. Tomohiro Tsuchida and Dr. Shoichi Saito (JFCR) for collecting human specimens, Ms. Yuko Wakabayashi, Ms. Tamae Kondo, Ms. Masae Suzuki (Osaka University), Ms. Satoko Baba and Dr. Ryoji Yao (JFCR) for technical supports throughout this study. We are grateful to Dr. Toshiki Mukai, Dr. Tomohiro Yamaguchi, Dr. Toshiya Nagasaki, Dr. Takashi Akiyoshi, Dr. Tsuyoshi Konishi (JFCR) and members of Hara’s laboratory for helpful discussion during the preparation of this manuscript. This work was supported in part by grants from the Japan Agency of Medical Research and Development (AMED) under grant numbers 19gm501000h0003 and 19cm0106401h0004, from the Japan Science and Technology Agency (JST) under grant number JPMJMS2022 and from the Japan Society for the Promotion of Science (JSPS) under grant numbers 19K16612, 18K15065, 16H06276 (AdAMS), 26250028 and 18K15188. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Emerging evidence is revealing that alterations in gut microbiota are associated with colorectal cancer (CRC). However, very little is currently known about whether and how gut microbiota alterations are causally associated with CRC development. Here we show that 12 faecal bacterial taxa are enriched in CRC patients in two independent cohort studies. Among them, 2 Porphyromonas species are capable of inducing cellular senescence, an oncogenic stress response, through the secretion of the bacterial metabolite, butyrate. Notably, the invasion of these bacteria is observed in the CRC tissues, coinciding with the elevation of butyrate levels and signs of senescence-associated inflammatory phenotypes. Moreover, although the administration of these bacteria into ApcΔ14/+ mice accelerate the onset of colorectal tumours, this is not the case when bacterial butyrate-synthesis genes are disrupted. These results suggest a causal relationship between Porphyromonas species overgrowth and colorectal tumourigenesis which may be due to butyrate-induced senescence.

AB - Emerging evidence is revealing that alterations in gut microbiota are associated with colorectal cancer (CRC). However, very little is currently known about whether and how gut microbiota alterations are causally associated with CRC development. Here we show that 12 faecal bacterial taxa are enriched in CRC patients in two independent cohort studies. Among them, 2 Porphyromonas species are capable of inducing cellular senescence, an oncogenic stress response, through the secretion of the bacterial metabolite, butyrate. Notably, the invasion of these bacteria is observed in the CRC tissues, coinciding with the elevation of butyrate levels and signs of senescence-associated inflammatory phenotypes. Moreover, although the administration of these bacteria into ApcΔ14/+ mice accelerate the onset of colorectal tumours, this is not the case when bacterial butyrate-synthesis genes are disrupted. These results suggest a causal relationship between Porphyromonas species overgrowth and colorectal tumourigenesis which may be due to butyrate-induced senescence.

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Gut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion

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