Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome

Shin Yoshimoto, Tze Mun Loo, Koji Atarashi, Hiroaki Kanda, Seidai Sato, Seiichi Oyadomari, Yoichiro Iwakura, Kenshiro Oshima, Hidetoshi Morita, Masahira Hattori, Kenya Honda, Yuichi Ishikawa, Eiji Hara, Naoko Ohtani

Research output: Contribution to journalArticle

750 Citations (Scopus)

Abstract

Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer. As the worldwide obesity epidemic has shown no signs of abating, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP) has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage. The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the DCA-SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis, indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.

Original languageEnglish
Pages (from-to)97-101
Number of pages5
JournalNature
Volume499
Issue number7456
DOIs
Publication statusPublished - 2013
Externally publishedYes

Fingerprint

Liver Neoplasms
Obesity
Hepatocellular Carcinoma
Hepatic Stellate Cells
Deoxycholic Acid
Phenotype
Neoplasms
Enterohepatic Circulation
Obese Mice
Human Development
Fatty Liver
Developed Countries
Carcinogens
DNA Damage
Bacteria
Liver

ASJC Scopus subject areas

  • General

Cite this

Yoshimoto, S., Loo, T. M., Atarashi, K., Kanda, H., Sato, S., Oyadomari, S., ... Ohtani, N. (2013). Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature, 499(7456), 97-101. https://doi.org/10.1038/nature12347

Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. / Yoshimoto, Shin; Loo, Tze Mun; Atarashi, Koji; Kanda, Hiroaki; Sato, Seidai; Oyadomari, Seiichi; Iwakura, Yoichiro; Oshima, Kenshiro; Morita, Hidetoshi; Hattori, Masahira; Honda, Kenya; Ishikawa, Yuichi; Hara, Eiji; Ohtani, Naoko.

In: Nature, Vol. 499, No. 7456, 2013, p. 97-101.

Research output: Contribution to journalArticle

Yoshimoto, S, Loo, TM, Atarashi, K, Kanda, H, Sato, S, Oyadomari, S, Iwakura, Y, Oshima, K, Morita, H, Hattori, M, Honda, K, Ishikawa, Y, Hara, E & Ohtani, N 2013, 'Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome', Nature, vol. 499, no. 7456, pp. 97-101. https://doi.org/10.1038/nature12347
Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499(7456):97-101. https://doi.org/10.1038/nature12347
Yoshimoto, Shin ; Loo, Tze Mun ; Atarashi, Koji ; Kanda, Hiroaki ; Sato, Seidai ; Oyadomari, Seiichi ; Iwakura, Yoichiro ; Oshima, Kenshiro ; Morita, Hidetoshi ; Hattori, Masahira ; Honda, Kenya ; Ishikawa, Yuichi ; Hara, Eiji ; Ohtani, Naoko. / Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. In: Nature. 2013 ; Vol. 499, No. 7456. pp. 97-101.
@article{35cfaa83190840288259c7b5ad955b6f,
title = "Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome",
abstract = "Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer. As the worldwide obesity epidemic has shown no signs of abating, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP) has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage. The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the DCA-SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis, indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.",
author = "Shin Yoshimoto and Loo, {Tze Mun} and Koji Atarashi and Hiroaki Kanda and Seidai Sato and Seiichi Oyadomari and Yoichiro Iwakura and Kenshiro Oshima and Hidetoshi Morita and Masahira Hattori and Kenya Honda and Yuichi Ishikawa and Eiji Hara and Naoko Ohtani",
year = "2013",
doi = "10.1038/nature12347",
language = "English",
volume = "499",
pages = "97--101",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7456",

}

TY - JOUR

T1 - Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome

AU - Yoshimoto, Shin

AU - Loo, Tze Mun

AU - Atarashi, Koji

AU - Kanda, Hiroaki

AU - Sato, Seidai

AU - Oyadomari, Seiichi

AU - Iwakura, Yoichiro

AU - Oshima, Kenshiro

AU - Morita, Hidetoshi

AU - Hattori, Masahira

AU - Honda, Kenya

AU - Ishikawa, Yuichi

AU - Hara, Eiji

AU - Ohtani, Naoko

PY - 2013

Y1 - 2013

N2 - Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer. As the worldwide obesity epidemic has shown no signs of abating, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP) has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage. The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the DCA-SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis, indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.

AB - Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer. As the worldwide obesity epidemic has shown no signs of abating, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP) has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage. The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the DCA-SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis, indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.

UR - http://www.scopus.com/inward/record.url?scp=84879888338&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879888338&partnerID=8YFLogxK

U2 - 10.1038/nature12347

DO - 10.1038/nature12347

M3 - Article

VL - 499

SP - 97

EP - 101

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7456

ER -