Skip to main content

Advertisement

SpringerLink
Log in

Baicalein, an enteric microbial metabolite, suppresses gut inflammation and cancer progression in ApcMin/+ mice

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Objective

Chronic inflammation is recognized as a risk factor for colorectal cancer (CRC) development. Baicalin (BI), a major constituent in an anti-inflammatory herb Scutellaria baicalensis, can be biotransformed into baicalein (BE) by the intestinal microbiota. We evaluated the anti-inflammation and anti-CRC effects of the metabolite BE.

Methods

The in vitro biotransformation by human intestinal microbiota from BI into BE has been determined with HPLC. Using a gut-specific ApcMin/+ mouse model, the effects of oral BE on the life span, organ index, and tumor multiplicity were evaluated. The expressions of inflammatory cytokines were determined using ELISA. To verify the in vivo data, the anti-inflammatory and antiproliferative effects of BE were determined with an in vitro cell model.

Results

HPLC analysis showed that BI was quickly transformed into BE by the intestinal microbiota. Oral BE (30 mg/kg/day) significantly increased the life span, from 125.2 to 218.4 days (P < 0.01%). BE treatment also decreased intestine index and increased spleen index. Compared with the model group, following BE treatment, tumor numbers were significantly reduced in the small intestine and colon (P < 0.01, P < 0.05, respectively). In the gut tissues, BE treatment significantly reduced inflammatory cytokine levels such as IL-1β, IL-2, IL-6, IL-10, G-CSF, and GM-CSF. In vitro data supported our in vivo results that the anti-CRC effects of BE were via the inhibition of gut inflammation and induction of cancer cell death.

Conclusion

Our results suggest that the parent compound BI can be quickly converted into its microbial metabolite BE, which has stronger bioactive effects than BI. Baicalein is an active chemopreventive metabolite for inflammatory associated CRC.

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

Similar content being viewed by others

References

  1. Fillon M. Study aims to improve colorectal cancer screening rates. CA Cancer J Clin. 2019;69(3):161–3.

    Article  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.

    Google Scholar 

  3. McCarthy N. Tumorigenesis: all together now. Nat Rev Cancer. 2013;13(3):148–9.

    Article  CAS  Google Scholar 

  4. Madka V, Rao CV. Anti-inflammatory phytochemicals for chemoprevention of colon cancer. Curr Cancer Drug Targets. 2013;13(5):542–57.

    Article  CAS  Google Scholar 

  5. Fang R, Wu R, Zuo Q, Yin R, Zhang C, Wang C, et al. Sophora flavescens containing-QYJD formula activates Nrf2 anti-oxidant response, blocks cellular transformation and protects against DSS-induced colitis in mouse model. Am J Chin Med. 2018;46(7):1609–23.

    Article  CAS  Google Scholar 

  6. Cragg GM, Grothaus PG, Newman DJ. Impact of natural products on developing new anti-cancer agents. Chem Rev. 2009;109(7):3012–43.

    Article  CAS  Google Scholar 

  7. Li-Weber M. New therapeutic aspects of flavones: the anticancer properties of Scutellaria and its main active constituents Wogonin Baicalein and Baicalin. Cancer Treat Rev. 2009;35(1):57–68.

    Article  CAS  Google Scholar 

  8. Kim EH, Shim B, Kang S, Jeong G, Lee JS, Yu YB, et al. Anti-inflammatory effects of Scutellaria baicalensis extract via suppression of immune modulators and MAP kinase signaling molecules. J Ethnopharmacol. 2009;126(2):320–31.

    Article  Google Scholar 

  9. Wang CZ, Li XL, Wang QF, Mehendale SR, Yuan CS. Selective fraction of Scutellaria baicalensis and its chemopreventive effects on MCF-7 human breast cancer cells. Phytomedicine. 2010;17(1):63–8.

    Article  CAS  Google Scholar 

  10. Wang CZ, Zhang CF, Chen L, Anderson S, Lu F, Yuan CS. Colon cancer chemopreventive effects of baicalein, an active enteric microbiome metabolite from baicalin. Int J Oncol. 2015;47(5):1749–58.

    Article  CAS  Google Scholar 

  11. Yu C, Zhang Z, Zhang H, Zhen Z, Calway T, Wang Y, et al. Pretreatment of baicalin and wogonoside with glycoside hydrolase: a promising approach to enhance anticancer potential. Oncol Rep. 2013;30(5):2411–8.

    Article  CAS  Google Scholar 

  12. Shen J, Cao C, Su H, Yang X, Wei Z, Du L. Evidence of gastro-intestinal system as an active and toxic target of sasanqua saponins extract. Exp Toxicol Pathol. 2008;60(1):43–9.

    Article  CAS  Google Scholar 

  13. Dworzanski T, Celinski K, Korolczuk A, Slomka M, Radej S, Czechowska G, et al. Influence of the peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, rosiglitazone and antagonist, biphenol-A-diglicydyl ether (BADGE) on the course of inflammation in the experimental model of colitis in rats. J Physiol Pharmacol. 2010;61(6):683–93.

    CAS  PubMed  Google Scholar 

  14. Dong N, Xu X, Xue C, Wang C, Li X, Shan A, et al. Ethyl pyruvate protects against Salmonella intestinal infection in mice through down-regulation of pro-inflammatory factors and inhibition of TLR4/MAPK pathway. Int Immunopharmacol. 2019;71(1):155–63.

    Article  CAS  Google Scholar 

  15. Zhou Y, Boudreau DM, Freedman AN. Trends in the use of aspirin and nonsteroidal anti-inflammatory drugs in the general US population. Pharmacoepidemiol Drug Saf. 2014;23(1):43–50.

    Article  CAS  Google Scholar 

  16. Aggarwal BB, Van Kuiken ME, Iyer LH, Harikumar KB, Sung B. Molecular targets of nutraceuticals derived from dietary spices: potential role in suppression of inflammation and tumorigenesis. Exp Biol Med (Maywood). 2009;234(8):825–49.

    Article  CAS  Google Scholar 

  17. Li Q, Shan Q, Sang X, Zhu R, Chen X, Cao G. Total glycosides of peony protects against inflammatory bowel disease by regulating IL-23/IL-17 axis and Th17/Treg balance. Am J Chin Med. 2019;47(1):177–201.

    Article  CAS  Google Scholar 

  18. Cheng CS, Chen J, Tan HY, Wang N, Chen Z, Feng Y. Scutellaria baicalensis and cancer treatment: recent progress and perspectives in biomedical and clinical studies. Am J Chin Med. 2018;46(1):25–54.

    Article  CAS  Google Scholar 

  19. Kim HI, Hong SH, Ku JM, Lim YS, Lee SJ, Song J, et al. Scutellaria radix promotes apoptosis in non-small cell lung cancer cells via induction of AMPK-dependent autophagy. Am J Chin Med. 2019;47(3):691–705.

    Article  CAS  Google Scholar 

  20. Kim H, Jung BJ, Jung JH, Kim JY, Chung SK, Chung DK. Lactobacillus plantarum lipoteichoic acid alleviates TNF-alpha-induced inflammation in the HT-29 intestinal epithelial cell line. Mol Cells. 2012;33(5):479–86.

    Article  CAS  Google Scholar 

  21. Compare D, Nardone G. Contribution of gut microbiota to colonic and extracolonic cancer development. Dig Dis. 2011;29(6):554–61.

    Article  Google Scholar 

  22. Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and disease. Physiol Rev. 2010;90(3):859–904.

    Article  CAS  Google Scholar 

  23. Holmes E, Kinross J, Gibson GR, Burcelin R, Jia W, Pettersson S, et al. Therapeutic modulation of microbiota-host metabolic interactions. Sci Transl Med. 2012;4(137):137rv6.

    Article  Google Scholar 

  24. Wang CZ, Huang WH, Zhang CF, Wan JY, Wang Y, Yu C, et al. Role of intestinal microbiome in American ginseng-mediated colon cancer prevention in high fat diet-fed AOM/DSS mice. Clin Transl Oncol. 2018;20(3):302–12.

    Article  CAS  Google Scholar 

  25. Day SD, Enos RT, McClellan JL, Steiner JL, Velazquez KT, Murphy EA. Linking inflammation to tumorigenesis in a mouse model of high-fat-diet-enhanced colon cancer. Cytokine. 2013;64(1):454–62.

    Article  CAS  Google Scholar 

  26. Jacoby RF, Seibert K, Cole CE, Kelloff G, Lubet RA. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. Cancer Res. 2000;60(18):5040–4.

    CAS  PubMed  Google Scholar 

  27. Pharmacopoeia_Committee_of_China. The Chinese Pharmacopoeia, 2015 Edition, vol 1. Beijing: China Medical Science and Technology Press; 2015.

    Google Scholar 

  28. Li M, Shi A, Pang H, Xue W, Li Y, Cao G, et al. Safety, tolerability, and pharmacokinetics of a single ascending dose of baicalein chewable tablets in healthy subjects. J Ethnopharmacol. 2014;156(1):210–5.

    Article  CAS  Google Scholar 

  29. Long X, Ye Y, Zhang L, Liu P, Yu W, Wei F, et al. IL-8, a novel messenger to cross-link inflammation and tumor EMT via autocrine and paracrine pathways. Int J Oncol. 2016;48(1):5–12.

    Article  CAS  Google Scholar 

  30. Le Bivic A, Hirn M, Reggio H. HT-29 cells are an in vitro model for the generation of cell polarity in epithelia during embryonic differentiation. Proc Natl Acad Sci USA. 1988;85(1):136–40.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported in part by NIH/NCCAM Grants P01 AT004418 and K01 AT005362; Chinese Grants from the 111 Project from the Ministry of Education of China and the State Administration of Foreign Experts Affairs of China (B16046), National Natural Science Foundation of China (81603378), and Natural Science Foundation of Jiangsu Province (BK20160545).

Author information

Authors and Affiliations

  1. Tang Center for Herbal Medicine Research, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL, 60637, USA

    C.-Z. Wang, C.-F. Zhang, Y. Luo, H. Yao, C. Yu, L. Chen, J. Yuan, W.-H. Huang, J.-Y. Wan, J. Zeng, W. R. Sawadogo & C.-S. Yuan

  2. Department of Anesthesia and Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, IL, 60637, USA

    C.-Z. Wang, C.-F. Zhang, Y. Luo, H. Yao, C. Yu, L. Chen, J. Yuan, W.-H. Huang, J.-Y. Wan, J. Zeng, W. R. Sawadogo & C.-S. Yuan

  3. Committee on Clinical Pharmacology and Pharmacogenomics, Pritzker School of Medicine, University of Chicago, Chicago, IL, 60637, USA

    C.-S. Yuan

Authors
  1. C.-Z. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C.-F. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y. Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H. Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. W.-H. Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J.-Y. Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J. Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. W. R. Sawadogo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. C.-S. Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CZW and CSY designed the study, set up the experiments, participated in data collection, analyzed and interpreted the results, and drafted the manuscript. CFZ, HY, CY, LC, JY, WHH, JYW, and JZ carried out some experiments and participated in the related data interpretations. CZW, CSY, YL and WRS revised the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to C.-Z. Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

The use and care of animals were implemented with consideration of the guidelines approved by the Institutional Animal Care and Use Committee at the University of Chicago (ACUP number: 70917, approved on February 12, 2015).

Informed consent

The research did not involve human participants.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, CZ., Zhang, CF., Luo, Y. et al. Baicalein, an enteric microbial metabolite, suppresses gut inflammation and cancer progression in ApcMin/+ mice. Clin Transl Oncol 22, 1013–1022 (2020). https://doi.org/10.1007/s12094-019-02225-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-019-02225-5

Keywords

Search

Navigation