Skip to main content

Sodium butyrate modulates gut microbiota and immune response in colorectal cancer liver metastatic mice

Cell Biology and Toxicology volume 36, pages 509–515 (2020)Cite this article

Abstract

Colorectal cancer (CRC) liver metastasis (CLM) is the leading death cause of CRC patients, but there is no satisfied approach to treat CLM. Gut microbiota plays a pivotal role in CRC initiation and development. Targeting dysbiosis of the gut microbiota might open up new opportunities for CLM treatment. Here, we investigated the efficacy of sodium butyrate (NaB), a major product of gut microbial fermentation, in modulating gut microbiota in CLM mice. NaB supplement decreased mouse colon cancer CT26 cell liver metastasis in intrasplenic tumor injection model of BALB/c mice. Using 16S rRNA gene sequencing, we found altered microbiota composition in CLM mice, characterized by increases of Firmicutes and Proteobacteria. NaB beneficially changed dysbiosis in CLM mice. Functional analysis of the KEGG pathways showed that NaB changed pathways related to immune system diseases and primary immunodeficiency in CLM mice. In addition, NaB decreased T regulatory cells and increased natural killer T cells and T helper 17 cells, accordingly decreased IL-10 and increased IL-17 secretion in CLM mice liver. In conclusion, NaB beneficially modulated gut microbiota and improved host immune response in CLM mice. These findings demonstrate the therapeutic potential of NaB in CLM treatment.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

Abbreviations

NaB :

Sodium butyrate

CRC :

Colorectal cancer

CLM :

Colorectal liver metastasis

SCFAs :

Short-chain fatty acids

NK :

Natural killer

Treg :

T regulatory

Th17 :

T helper 17

References

  • Abdulamir AS, Hafidh RR, Abu BF. The association of Streptococcus bovis/gallolyticus with colorectal tumors: the nature and the underlying mechanisms of its etiological role. J Exp Clin Cancer Res. 2011;30:11–24.

    Article  Google Scholar 

  • Amicarella F, Muraro MG, Hirt C, Cremonesi E, Padovan E, Mele V, et al. Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer. Gut. 2017;66:692–704.

    CAS  Article  Google Scholar 

  • An D, Oh SF, Olszak T, Neves JF, Avci FY, Erturk-Hasdemir D, et al. Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells. Cell. 2014;156:123–33.

    CAS  Article  Google Scholar 

  • Balamurugan R, Rajendiran E, George S, Samuel GV, Ramakrishna BS. Real-time polymerase chain reaction quantification of specific butyrate-producing bacteria, Desulfovibrio and Enterococcus faecalis in the feces of patients with colorectal cancer. J Gastroenterol Hepatol. 2008;23:1298–303.

    CAS  Article  Google Scholar 

  • Bishehsari F, Engen PA, Preite NZ, Tuncil YE, Naqib A, Shaikh M, et al. Dietary fiber treatment corrects the composition of gut microbiota, promotes SCFA production, and suppresses colon carcinogenesis. Genes (Basel). 2018;9:E102.

    Article  Google Scholar 

  • Chen J, Wei Y, He J, Cui G, Zhu Y, Lu C, et al. Natural killer T cells play a necessary role in modulating of immune-mediated liver injury by gut microbiota. Sci Rep. 2014;4:7259–70.

    CAS  Article  Google Scholar 

  • Fang W, Xue H, Chen X, Chen K, Ling W. Supplementation with sodium butyrate modulates the composition of the gut microbiota and ameliorates high-fat diet-induced obesity in mice. J Nutr. 2019;149:747–54.

    Article  Google Scholar 

  • Fessler J, Matson V, Gajewski TF. Exploring the emerging role of the microbiome in cancer immunotherapy. J Immunother Cancer. 2019;7:108–33.

    Article  Google Scholar 

  • Flemer B, Lynch DB, Brown JM, Jeffery IB, Ryan FJ, Claesson MJ, et al. Tumour-associated and non-tumour-associated microbiota in colorectal cancer. Gut. 2017;66:633–43.

    CAS  Article  Google Scholar 

  • Ibrahim A, Hugerth LW, Hases L, Saxena A, Seifert M, Thomas Q, et al. Colitis-induced colorectal cancer and intestinal epithelial estrogen receptor beta impact gut microbiota diversity. Int J Cancer. 2019;144:3086–98.

    CAS  Article  Google Scholar 

  • Li R, Zhou R, Wang H, Li W, Pan M, Yao X, et al. Gut microbiota-stimulated cathepsin K secretion mediates TLR4-dependent M2 macrophage polarization and promotes tumor metastasis in colorectal cancer. Cell Death Differ. 2019;26:2447–63.

    CAS  Article  Google Scholar 

  • Ling KL, Pratap SE, Bates GJ, Singh B, Mortensen NJ, George BD, et al. Increased frequency of regulatory T cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients. Cancer Immun. 2007;7:7–14.

    PubMed  PubMed Central  Google Scholar 

  • Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018;360:eaan5931.

    Article  Google Scholar 

  • Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14:1208–15.

    CAS  Article  Google Scholar 

  • Snezhkina AV, Krasnov GS, Lipatova AV, Sadritdinova AF, Kardymon OL, Fedorova MS, et al. The dysregulation of polyamine metabolism in colorectal cancer is associated with overexpression of c-Myc and C/EBPβ rather than enterotoxigenic Bacteroides fragilis infection. Oxidative Med Cell Longev. 2016;2016 United States:2353560.

    Article  Google Scholar 

  • Wang C, Yang S, Gao L, Wang L, Cao L. Carboxymethyl pachyman (CMP) reduces intestinal mucositis and regulates the intestinal microflora in 5-fluorouracil-treated CT26 tumour-bearing mice. Food Funct. 2018;9:2695–704.

    CAS  Article  Google Scholar 

  • Wang G, Yu Y, Wang YZ, Wang JJ, Guan R, Sun Y, et al. Role of SCFAs in gut microbiome and glycolysis for colorectal cancer therapy. J Cell Physiol. 2019;234:17023–49.

    CAS  Article  Google Scholar 

  • Wirbel J, Pyl PT, Kartal E, Zych K, Kashani A, Milanese A, et al. Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer. Nat Med. 2019;25:679–89.

    CAS  Article  Google Scholar 

  • Wong SH, Zhao L, Zhang X, Nakatsu G, Han J, Xu W, et al. Gavage of fecal samples from patients with colorectal cancer promotes intestinal carcinogenesis in germ-free and conventional mice. Gastroenterology. 2017;153:1621–1633.e6.

    Article  Google Scholar 

  • Wu GD, Compher C, Chen EZ, Smith SA, Shah RD, Bittinger K, et al. Comparative metabolomics in vegans and omnivores reveal constraints on diet-dependent gut microbiota metabolite production. Gut. 2016;65:63–72.

    CAS  Article  Google Scholar 

  • Yang Y, Jobin C. Novel insights into microbiome in colitis and colorectal cancer. Curr Opin Gastroenterol. 2017;33:422–7.

    CAS  Article  Google Scholar 

  • Zhang Y, Kang C, Wang XL, Zhou M, Chen MT, Zhu XH, et al. Dietary factors modulate colonic tumorigenesis through the interaction of gut microbiota and host chloride channels. Mol Nutr Food Res 2018; 62.

Download references

Acknowledgments

We thank Dr. Guoqi Liu for gut microbiota assays.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81272493, No. 81472213), the Health Commission of Zhejiang Province (No. 2019331258, No. 2019335600), the Natural Sciences Foundation of Zhejiang Province (No. LY17H220001), and the Science Technology Department of Zhejiang Province (No. GF20H220003, No. 2015C37112).

Author information

Author notes

  1. Ximei Ma and Zhuha Zhou contributed equally to this work.

Affiliations

  1. Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    Ximei Ma, Zhuha Zhou & Guanyu Wang

  2. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    Xujun Zhang & Hongyan Diao

  3. Central Lab of Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    Mengjing Fan, Yiyang Hong & Qinghua Dong

  4. Institute of Translational Medicine, School of Medicine, Zhejiang University|, Hangzhou, Zhejiang, China

    Ye Feng

  5. Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou, Zhejiang, China

    Qinghua Dong

Authors
  1. Ximei Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhuha Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xujun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mengjing Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yiyang Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ye Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qinghua Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hongyan Diao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Guanyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G. W., Q. D., and H. D. participated in the design of the study. X. M., Z. Z., Z. X., M. F., and Y. H. performed the experiments. Q. D., G. W., X. M., Z. Z., Y. F., and H. D. contributed to data interpretation and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Qinghua Dong, Hongyan Diao or Guanyu Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher’s note

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

Electronic supplementary material

ESM 1

(DOC 26786 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ma, X., Zhou, Z., Zhang, X. et al. Sodium butyrate modulates gut microbiota and immune response in colorectal cancer liver metastatic mice. Cell Biol Toxicol 36, 509–515 (2020). https://doi.org/10.1007/s10565-020-09518-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10565-020-09518-4

Keywords

  • Sodium butyrate
  • Colorectal cancer
  • Liver metastasis
  • Gut microbiota
  • Immunity