Letter | Published:

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

Nature volume 499, pages 97101 (04 July 2013) | Download Citation

Subjects

  • 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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Accessions

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.

References

  1. 1.

    , & Molecular mechanisms of cancer development in obesity. Nature Rev. Cancer 11, 886–895 (2011)

  2. 2.

    & Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Rev. Cancer 4, 579–591 (2004)

  3. 3.

    & Obesity, inflammation, and liver cancer. J. Hepatol. 56, 704–713 (2012)

  4. 4.

    et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008)

  5. 5.

    & Senescence-messaging secretome: SMS-ing cellular stress. Nature Rev. Cancer 9, 81–94 (2009)

  6. 6.

    , & Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 47, 241–259 (2006)

  7. 7.

    Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 88, 125–172 (2008)

  8. 8.

    , , , & Cell surface-bound IL-1α is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proc. Natl Acad. Sci. USA 106, 17031–17036 (2009)

  9. 9.

    & Senescence in tumours: evidence from mice and humans. Nature Rev. Cancer 10, 51–57 (2010)

  10. 10.

    , , & The essence of senescence. Genes Dev. 24, 2463–2479 (2010)

  11. 11.

    et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008)

  12. 12.

    et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011)

  13. 13.

    et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208 (2010)

  14. 14.

    et al. Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo. J. Hepatol. 51, 725–733 (2009)

  15. 15.

    et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell 85, 27–37 (1996)

  16. 16.

    et al. Visualizing the dynamics of p21Waf1/Cip1 cyclin-dependent kinase inhibitor expression in living animals. Proc. Natl Acad. Sci. USA 104, 15034–15039 (2007)

  17. 17.

    et al. Tumor suppressor and aging biomarker p16INK4a induces cellular senescence without the associated inflammatory secretory phenotype. J. Biol. Chem. 286, 36396–36403 (2011)

  18. 18.

    et al. Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone. Nature Biotechnol. 26, 431–442 (2008)

  19. 19.

    , , & Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006)

  20. 20.

    et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012)

  21. 21.

    et al. Deoxycholate induces mitochondrial oxidative stress and activates NF-κB through multiple mechanisms in HCT-116 colon epithelial cells. Carcinogenesis 28, 215–222 (2007)

  22. 22.

    et al. DNA damage signaling triggers degradation of histone methyltransferases through APC/CCdh1 in senescent cells. Mol. Cell 45, 123–131 (2012)

  23. 23.

    , & Diet, anaerobic bacterial metabolism, and colon cancer: a review of the literature. J. Clin. Gastroenterol. 39, 98–109 (2005)

  24. 24.

    et al. Enhanced preneoplastic liver lesion development under ‘selection pressure’ conditions after administration of deoxycholic or lithocholic acid in the initiation phase in rats. Carcinogenesis 11, 1323–1328 (1990)

  25. 25.

    , , , & Effects of ingestion of difructose anhydride III (DFA III) and the DFA III-assimilating bacterium Ruminococcus productus on rat intestine. Biosci. Biotechnol. Biochem. 70, 332–339 (2006)

  26. 26.

    Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat. Clin. Pract. Gastroenterol. Hepatol. 3, 318–328 (2006)

  27. 27.

    & Identification and characterization of two bile acid coenzyme A transferases from Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium. J. Lipid Res. 53, 66–76 (2012)

  28. 28.

    , , , & Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype. Hepatology 37, 653–664 (2003)

  29. 29.

    & Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our case series and literature review. World J. Gastroenterol. 16, 1436–1441 (2010)

  30. 30.

    et al. Cellular toxicity of fecal water depends on diet. Am. J. Clin. Nutr. 45, 559–563 (1987)

  31. 31.

    et al. Production of mice deficient in genes for interleukin (IL)-1α, IL-1β, IL-1α/β, and IL-1 receptor antagonist shows that IL-1β is crucial in turpentine-induced fever development and glucocorticoid secretion. J. Exp. Med. 187, 1463–1475 (1998)

  32. 32.

    , & Dose translation from animal to human studies revisited. FASEB J. 22, 659–661 (2008)

  33. 33.

    et al. Real-time in vivo imaging of p16Ink4a reveals cross talk with p53. J. Cell Biol. 186, 393–407 (2009)

  34. 34.

    et al. The phylogeny of the genus Clostridium: proposal of five new general and eleven new species combinations. Int. J. Syst. Bacteriol. 44, 812–826 (1994)

  35. 35.

    et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011)

  36. 36.

    , & Real-time PCR quantitation of clostridia in feces of autistic children. Appl. Environ. Microbiol. 70, 6459–6465 (2004)

  37. 37.

    et al. Metabolomic anatomy of an animal model revealing homeostatic imbalances in dyslipidaemia. Mol. Biosyst. 7, 1217–1223 (2011)

  38. 38.

    et al. Detection of Δ4-3-oxo-steroid 5β-reductase deficiency by LC–ESI-MS/MS measurement of urinary bile acids. J. Chromatogr. B 900, 24–31 (2012)

  39. 39.

    et al. Down-regulation of cyclin E1 expression by microRNA-195 accounts for interferon-β-induced inhibition of hepatic stellate cell proliferation. J. Cell. Physiol. 226, 2535–2542 (2011)

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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.

Author information

Author notes

    • Shin Yoshimoto
    •  & Naoko Ohtani

    These authors contributed equally to this work.

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Eiji Hara.

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DOI

https://doi.org/10.1038/nature12347

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