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

Nature volume 499, pages 97–101 (2013)Cite this article

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A Corrigendum to this article was published on 29 January 2014

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 cancer1. As the worldwide obesity epidemic has shown no signs of abating2, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer1,3, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP)4,5 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 damage6. The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs)7, 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 inducer8 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 steatohepatitis3, 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.

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Figure 1: Cellular senescence in HSCs.
Figure 2: IL-1β deficiency alleviates obesity-induced HCC development.
Figure 3: Antibiotics treatments alleviate obesity-induced HCC development.
Figure 4: Bacterial metabolite promotes obesity-induced HCC development.

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DDBJ/GenBank/EMBL

Data deposits

Bacterial 16S rRNA amplicon sequence data have been deposited in DDBJ (http://www.ddbj.nig.ac.jp/index-e.html) with the accession number DRA000952.

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Acknowledgements

The authors thank M. Oshima for suggestions in antibiotics treatment and members of the Hara laboratory for discussion during the preparation of this manuscript. This work was supported by grants from Japan Science and Technology Agency (JST), Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), Ministry of Health, Labour and Welfare of Japan (MHLW), Uehara Memorial Foundation and Takeda Science Foundation. S.Y. was partly supported by a postdoctoral fellowship from the Japan Society for Promotion of Science (JSPS). T.M.L. was partly supported by an international scholarship from the Ajinomoto Scholarship Foundation.

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Author notes

  1. Shin Yoshimoto and Naoko Ohtani: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan,

    Shin Yoshimoto, Tze Mun Loo, Seidai Sato, Eiji Hara & Naoko Ohtani

  2. CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan,

    Shin Yoshimoto, Tze Mun Loo, Seidai Sato, Kenya Honda & Eiji Hara

  3. Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba 278-8510, Japan,

    Tze Mun Loo

  4. Research Center for Allergy and Immunology, RIKEN, Yokohama, Kanagawa 230-0045, Japan,

    Koji Atarashi & Kenya Honda

  5. PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan,

    Koji Atarashi & Naoko Ohtani

  6. Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan,

    Hiroaki Kanda & Yuichi Ishikawa

  7. Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan,

    Seiichi Oyadomari

  8. Research Institute for Biological Science, Tokyo University of Science, Noda, Chiba 278-8510, Japan,

    Yoichiro Iwakura

  9. Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba 277-8561, Japan,

    Kenshiro Oshima & Masahira Hattori

  10. School of Veterinary Medicine, Azabu University, Sagamihara, Kanagawa 229-8501, Japan,

    Hidetoshi Morita

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Contributions

E.H. and N.O. designed the experiments, analysed the data and wrote the manuscript. N.O., S.Y. and T.M.L. performed obesity-induced liver cancer experiments. K.A., K.O., H.M., M.H. and K.H. performed bacterial genome data analysis. H.K., S.S. and Y.I. performed histopathological analysis of mouse and human liver cancer specimens. S.O. performed metabolite analysis. Y.I. provided Il-1β−/− mice. E.H. oversaw the projects.

Corresponding author

Correspondence to Eiji Hara.

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The authors declare no competing financial interests.

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Yoshimoto, S., Loo, T., Atarashi, K. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013). https://doi.org/10.1038/nature12347

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