Skip to main content

Advertisement

SpringerLink
Log in

Clostridium butyricum and its metabolite butyrate promote ferroptosis susceptibility in pancreatic ductal adenocarcinoma

  • Research
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Purpose

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited therapeutic options. The diversity and composition of the intratumoral microbiota are associated with PDAC outcomes, and modulating the tumor microbiota has the potential to influence tumor growth and the host immune response. Here, we explore whether intervention with butyrate-producing probiotics can limit PDAC progression.

Methods

Based on the TCGA (PAAD) database, we analyzed the differential communities of intratumoral microbiota in PDAC patients with long survival and short survival and explored the relevant mechanisms of Clostridium butyricum and its metabolite butyrate in the treatment of PDAC. Treatment with Clostridium butyricum or butyrate in combination with the ferroptosis inducer RSL3 in a PDAC mouse model has an inhibitory effect on PDAC progression. The potential molecular mechanisms were verified by flow cytometry, RNA-seq, Western blotting, qRT‒PCR and immunofluorescence.

Results

We found that the tumoral butyrate-producing microbiota was linked to a better prognosis and less aggressive features of PDAC. Intervention with Clostridium butyricum or its metabolite butyrate triggered superoxidative stress and intracellular lipid accumulation, which enhanced ferroptosis susceptibility in PDAC.

Conclusion

Our study reveals a novel antitumor mechanism of butyrate and suggests the therapeutic potential of butyrate-producing probiotics in PDAC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request (GSE227418).

References

  1. P. Rawla, T. Sunkara, V. Gaduputi, Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J. Oncol. 10, 10–27 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  2. A. Rebelo, C.W. Michalski, J. Ukkat, J. Kleeff, Pancreatic cancer surgery with vascular resection: current concepts and perspectives. J. Pancreatol. 2, 1–5 (2019)

    Article  Google Scholar 

  3. W. Wu, G. Jin, C. Wang, Y. Miao, H. Wang, W. Lou, X. Yu, B. Sun, H. Li, R. Qin, Z. Wu, W. Wang, K. Xu, L. Wang, T. Liang, C. Hao, H. Huang, Y. Li, G. Tan, Y. Zhao, J. Hao, Y. Wang, C. Peng, X. Liu, J. Ou, C. Yuan, X. Wang, Y. Yang, S. Cai, K. Guo, J. Jiang, X. Yu, J. Wei, F. Li, X. Wu and Y. Zhao, The current surgical treatment of pancreatic cancer in China: a national wide cross-sectional study. J. Pancreatol. 2, 16–21 (2019)

  4. W. Wu, Q. Liu, J. Zhang, Y. Zhao, Survey on the current status of the diagnosis and treatment of pancreatic cancer in public tertiary hospitals in China: a cross-sectional questionnaire-based, observational study. J. Pancreatol. 4, 164–169 (2021)

    Article  Google Scholar 

  5. L.D. Wood, M.B. Yurgelun, M.G. Goggins, Genetics of familial and sporadic pancreatic cancer. Gastroenterology 156, 2041–2055 (2019)

    Article  CAS  PubMed  Google Scholar 

  6. C.P. Zambirinis, G. Miller, Cancer manipulation of host physiology: lessons from pancreatic cancer. Trends Mol. Med. 23, 465–481 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. J.L. Galeano Niño, H. Wu, K.D. LaCourse, A.G. Kempchinsky, A. Baryiames, B. Barber, N. Futran, J. Houlton, C. Sather, E. Sicinska, A. Taylor, S.S. Minot, C.D. Johnston, S. Bullman, Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature. 611, 810–817 (2022)

  8. B.A. Helmink, M.A.W. Khan, A. Hermann, V. Gopalakrishnan, J.A. Wargo, The microbiome, cancer, and cancer therapy. Nat. Med. 25, 377–388 (2019)

    Article  CAS  PubMed  Google Scholar 

  9. M. Stasiewicz, T.M. Karpiński, The oral microbiota and its role in carcinogenesis. Semin. Cancer Biol. 86, 633–642 (2022)

    Article  CAS  PubMed  Google Scholar 

  10. F. McAllister, M.A.W. Khan, B. Helmink, J.A. Wargo, The tumor microbiome in pancreatic cancer: bacteria and beyond. Cancer Cell 36, 577–579 (2019)

    Article  CAS  PubMed  Google Scholar 

  11. K. Hezaveh, R.S. Shinde, A. Klötgen, M.J. Halaby, S. Lamorte, M.T. Ciudad, R. Quevedo, L. Neufeld, Z.Q. Liu, R. Jin, B.T. Grünwald, E.G. Foerster, D. Chaharlangi, M. Guo, P. Makhijani, X. Zhang, T.J. Pugh, D.M. Pinto, I.L. Co, A.P. McGuigan, G.H. Jang, R. Khokha, P.S. Ohashi, G.M. O’Kane, S. Gallinger, W.W. Navarre, H. Maughan, D.J. Philpott, D.G. Brooks, T.L. McGaha, Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity. Immunity 55, 324-340.e328 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. E. Riquelme, Y. Zhang, L. Zhang, M. Montiel, M. Zoltan, W. Dong, P. Quesada, I. Sahin, V. Chandra, A. San Lucas, P. Scheet, H. Xu, S.M. Hanash, L. Feng, J.K. Burks, K.A. Do, C.B. Peterson, D. Nejman, C.D. Tzeng, M.P. Kim, C.L. Sears, N. Ajami, J. Petrosino, L.D. Wood, A. Maitra, R. Straussman, M. Katz, J.R. White, R. Jenq, J. Wargo, F. McAllister, Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell. 178, 795–806.e712 (2019)

  13. Y. Chen, S. Yang, J. Tavormina, D. Tampe, M. Zeisberg, H. Wang, K.K. Mahadevan, C.J. Wu, H. Sugimoto, C.C. Chang, R.R. Jenq, K.M. McAndrews, R. Kalluri, Oncogenic collagen I homotrimers from cancer cells bind to α3β1 integrin and impact tumor microbiome and immunity to promote pancreatic cancer. Cancer Cell 40, 818-834.e819 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. S. Pushalkar, M. Hundeyin, D. Daley, C.P. Zambirinis, E. Kurz, A. Mishra, N. Mohan, B. Aykut, M. Usyk, L.E. Torres, G. Werba, K. Zhang, Y. Guo, Q. Li, N. Akkad, S. Lall, B. Wadowski, J. Gutierrez, J.A. Kochen Rossi, J.W. Herzog, B. Diskin, A. Torres-Hernandez, J. Leinwand, W. Wang, P.S. Taunk, S. Savadkar, M. Janal, A. Saxena, X. Li, D. Cohen, R.B. Sartor, D. Saxena, G. Miller, The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression. Cancer Discov. 8, 403–416 (2018)

  15. W. He, J. Wu, J. Shi, Y.M. Huo, W. Dai, J. Geng, P. Lu, M.W. Yang, Y. Fang, W. Wang, Z.G. Zhang, A. Habtezion, Y.W. Sun, J. Xue, IL22RA1/STAT3 signaling promotes stemness and tumorigenicity in pancreatic cancer. Cancer Res. 78, 3293–3305 (2018)

    Article  CAS  PubMed  Google Scholar 

  16. G.D. Poore, E. Kopylova, Q. Zhu, C. Carpenter, S. Fraraccio, S. Wandro, T. Kosciolek, S. Janssen, J. Metcalf, S.J. Song, J. Kanbar, S. Miller-Montgomery, R. Heaton, R. McKay, S.P. Patel, A.D. Swafford, R. Knight, Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature 579, 567–574 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. M. Vital, A.C. Howe, J.M. Tiedje, Revealing the bacterial butyrate synthesis pathways by analyzing (meta) genomic data. mBio 5, e00889 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  18. L.T. Geller, M. Barzily-Rokni, T. Danino, O.H. Jonas, N. Shental, D. Nejman, N. Gavert, Y. Zwang, Z.A. Cooper, K. Shee, C.A. Thaiss, A. Reuben, J. Livny, R. Avraham, D.T. Frederick, M. Ligorio, K. Chatman, S.E. Johnston, C.M. Mosher, A. Brandis, G. Fuks, C. Gurbatri, V. Gopalakrishnan, M. Kim, M.W. Hurd, M. Katz, J. Fleming, A. Maitra, D.A. Smith, M. Skalak, J. Bu, M. Michaud, S.A. Trauger, I. Barshack, T. Golan, J. Sandbank, K.T. Flaherty, A. Mandinova, W.S. Garrett, S.P. Thayer, C.R. Ferrone, C. Huttenhower, S.N. Bhatia, D. Gevers, J.A. Wargo, T.R. Golub, R. Straussman, Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 357, 1156–1160 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. M.K. Stoeva, J. Garcia-So, N. Justice, J. Myers, S. Tyagi, M. Nemchek, P.J. McMurdie, O. Kolterman, J. Eid, Butyrate-producing human gut symbiont, Clostridium butyricum, and its role in health and disease. Gut Microbes. 13, 1–28 (2021)

    Article  PubMed  Google Scholar 

  20. T.C. Kenny, M.L. Gomez, D. Germain, Mitohormesis, UPR(mt), and the complexity of mitochondrial DNA landscapes in cancer. Cancer Res. 79, 6057–6066 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. K.C. Corn, M.A. Windham, M. Rafat, Lipids in the tumor microenvironment: From cancer progression to treatment. Prog. Lipid. Res. 80, 101055 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. J.J. Grachan, M. Kery, A.J. Giaccia, N.C. Denko and I. Papandreou, Lipid droplet storage promotes murine pancreatic tumor growth. Oncol. Rep. 45, 21 (2021)

  23. C.N. Rozeveld, K.M. Johnson, L. Zhang, G.L. Razidlo, KRAS Controls Pancreatic Cancer Cell Lipid Metabolism and Invasive Potential through the Lipase HSL. Cancer Res. 80, 4932–4945 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. M. Lafontan, D. Langin, Lipolysis and lipid mobilization in human adipose tissue. Prog. Lipid. Res. 48, 275–297 (2009)

    Article  CAS  PubMed  Google Scholar 

  25. E. Recazens, E. Mouisel, D. Langin, Hormone-sensitive lipase: sixty years later. Prog. Lipid. Res. 82, 101084 (2021)

    Article  CAS  PubMed  Google Scholar 

  26. B.R. Stockwell, Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell 185, 2401–2421 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. X. Chen, R. Kang, G. Kroemer, D. Tang, Broadening horizons: the role of ferroptosis in cancer. Nat. Rev. Clin. Oncol. 18, 280–296 (2021)

    Article  CAS  PubMed  Google Scholar 

  28. E.M. Park, M. Chelvanambi, N. Bhutiani, G. Kroemer, L. Zitvogel, J.A. Wargo, Targeting the gut and tumor microbiota in cancer. Nat. Med. 28, 690–703 (2022)

    Article  CAS  PubMed  Google Scholar 

  29. V. Matson, C.S. Chervin, T.F. Gajewski, Cancer and the microbiome-influence of the commensal microbiota on cancer, immune responses, and immunotherapy. Gastroenterology 160, 600–613 (2021)

    Article  CAS  PubMed  Google Scholar 

  30. T. Maekawa, R. Fukaya, S. Takamatsu, S. Itoyama, T. Fukuoka, M. Yamada, T. Hata, S. Nagaoka, K. Kawamoto, H. Eguchi, K. Murata, T. Kumada, T. Ito, M. Tanemura, K. Fujimoto, Y. Tomita, T. Tobe, Y. Kamada, E. Miyoshi, Possible involvement of Enterococcus infection in the pathogenesis of chronic pancreatitis and cancer. Biochem. Biophys. Res. Commun. 506, 962–969 (2018)

    Article  CAS  PubMed  Google Scholar 

  31. M.Y. Wei, S. Shi, C. Liang, Q.C. Meng, J. Hua, Y.Y. Zhang, J. Liu, B. Zhang, J. Xu, X.J. Yu, The microbiota and microbiome in pancreatic cancer: more influential than expected. Mol. Cancer. 18, 97 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  32. A. Koh, F. De Vadder, P. Kovatcheva-Datchary, F. Bäckhed, From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165, 1332–1345 (2016)

    Article  CAS  PubMed  Google Scholar 

  33. W.M. de Vos, H. Tilg, M. Van Hul, P.D. Cani, Gut microbiome and health: mechanistic insights. Gut 71, 1020–1032 (2022)

    Article  PubMed  Google Scholar 

  34. C. Panebianco, A. Villani, F. Pisati, F. Orsenigo, M. Ulaszewska, T.P. Latiano, A. Potenza, A. Andolfo, F. Terracciano, C. Tripodo, F. Perri, V. Pazienza, Butyrate, a postbiotic of intestinal bacteria, affects pancreatic cancer and gemcitabine response in in vitro and in vivo models. Biomed. Pharmacother. 151, 113163 (2022)

    Article  CAS  PubMed  Google Scholar 

  35. M. Luu, Z. Riester, A. Baldrich, N. Reichardt, S. Yuille, A. Busetti, M. Klein, A. Wempe, H. Leister, H. Raifer, F. Picard, K. Muhammad, K. Ohl, R. Romero, F. Fischer, C.A. Bauer, M. Huber, T.M. Gress, M. Lauth, S. Danhof, T. Bopp, T. Nerreter, I.E. Mulder, U. Steinhoff, M. Hudecek, A. Visekruna, Microbial short-chain fatty acids modulate CD8(+) T cell responses and improve adoptive immunotherapy for cancer. Nat. Commun. 12, 4077 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. F. Puca, F. Yu, C. Bartolacci, P. Pettazzoni, A. Carugo, E. Huang-Hobbs, J. Liu, C. Zanca, F. Carbone, E. Del Poggetto, J. Gumin, P. Dasgupta, S. Seth, S. Srinivasan, F.F. Lang, E.P. Sulman, P.L. Lorenzi, L. Tan, M. Shan, Z.P. Tolstyka, M. Kachman, L. Zhang, S. Gao, A.K. Deem, G. Genovese, P.P. Scaglioni, C.A. Lyssiotis, A. Viale, G.F. Draetta, Medium-chain acyl-CoA dehydrogenase protects mitochondria from lipid peroxidation in glioblastoma. Cancer Discov. 11, 2904–2923 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. G. Svegliati-Baroni, I. Pierantonelli, P. Torquato, R. Marinelli, C. Ferreri, C. Chatgilialoglu, D. Bartolini, F. Galli, Lipidomic biomarkers and mechanisms of lipotoxicity in non-alcoholic fatty liver disease. Free Radic. Biol. Med. 144, 293–309 (2019)

    Article  CAS  PubMed  Google Scholar 

  38. F. Canet, P. Díaz-Pozo, C. Luna-Marco, M. Fernandez-Reyes, T. Vezza, M. Marti, J.D. Salazar, I. Roldan, C. Morillas, S. Rovira-Llopis, M. Rocha, V.M. Víctor, Mitochondrial redox impairment and enhanced autophagy in peripheral blood mononuclear cells from type 1 diabetic patients. Redox. Biol. 58, 102551 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. D. Liang, A.M. Minikes, X. Jiang, Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol. Cell. 82, 2215–2227 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Y. Zhao, J. Li, W. Guo, H. Li, L. Lei, Periodontitis-level butyrate-induced ferroptosis in periodontal ligament fibroblasts by activation of ferritinophagy. Cell Death Discov. 6, 119 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Z. Bian, X. Sun, L. Liu, Y. Qin, Q. Zhang, H. Liu, L. Mao and S. Sun, Sodium Butyrate Induces CRC Cell Ferroptosis via the CD44/SLC7A11 Pathway and Exhibits a Synergistic Therapeutic Effect with Erastin. Cancers (Basel). 15, 423 (2023)

  42. M.A. Badgley, D.M. Kremer, H.C. Maurer, K.E. DelGiorno, H.J. Lee, V. Purohit, I.R. Sagalovskiy, A. Ma, J. Kapilian, C.E.M. Firl, A.R. Decker, S.A. Sastra, C.F. Palermo, L.R. Andrade, P. Sajjakulnukit, L. Zhang, Z.P. Tolstyka, T. Hirschhorn, C. Lamb, T. Liu, W. Gu, E.S. Seeley, E. Stone, G. Georgiou, U. Manor, A. Iuga, G.M. Wahl, B.R. Stockwell, C.A. Lyssiotis, K.P. Olive, Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 368, 85–89 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. S. Uchiyama, T. Shimizu, T. Shirasawa, CuZn-SOD deficiency causes ApoB degradation and induces hepatic lipid accumulation by impaired lipoprotein secretion in mice. J. Biol. Chem. 281, 31713–31719 (2006)

    Article  CAS  PubMed  Google Scholar 

  44. R.M. Lebovitz, H. Zhang, H. Vogel, J. Cartwright Jr., L. Dionne, N. Lu, S. Huang, M.M. Matzuk, Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc. Natl. Acad. Sci. U S A. 93, 9782–9787 (1996)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (No. 81970553, No. 81770628, No. 82022049, J. X); Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (No. 20161312, J.X.); Innovative Research Team of High-Level Local Universities in Shanghai (J.X.); 111 Projects (No. B21024, J.X.).

Author information

Author notes

  1. Xiaotong Yang and Zhengyan Zhang contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Systems Medicine for Cancer , Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai, 200127, China

    Xiaotong Yang, Zhengyan Zhang, Xuqing Shen, Junyi Xu, Yawen Weng & Jing Xue

  2. Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No 100, Haining Road, Shanghai, 200080, China

    Wei Wang

Authors
  1. Xiaotong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhengyan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xuqing Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Junyi Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yawen Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jing Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.X. and XT.Y. designed the experiment and interpreted the data; XT.Y. and ZY.Z. performed most of the experiments; XQ.S., JY.X. and YW.W. assisted in some experiments; W.W. provided the key materials and assisted in some discussion; J.X. and YX.T. wrote the manuscript; J.X. and W.W. provided overall guidance.

Corresponding authors

Correspondence to Wei Wang or Jing Xue.

Ethics declarations

Ethical approval

All animal experiments were approved by the Animal Care and Use Committees at Ren Ji Hospital (RJ2020-0505), Shanghai Jiao Tong University School of Medicine.

Competing interests

No potential conflict of interest was reported by the author(s).

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, X., Zhang, Z., Shen, X. et al. Clostridium butyricum and its metabolite butyrate promote ferroptosis susceptibility in pancreatic ductal adenocarcinoma. Cell Oncol. 46, 1645–1658 (2023). https://doi.org/10.1007/s13402-023-00831-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-023-00831-8

Keywords

Search

Navigation