Skip to main content
Log in

Sodium-Coupled Transport of the Short Chain Fatty Acid Butyrate by SLC5A8 and Its Relevance to Colon Cancer

  • ssat plenery presentation
  • Published:
Journal of Gastrointestinal Surgery



SLC5A8, expressed predominantly in the colon, is a Na+-coupled transporter for short-chain fatty acids. In this paper, we report on the characterization of butyrate transport by SLC5A8 and the relevance of SLC5A8-mediated butyrate transport to colon cancer.


SLC5A8 transports butyrate via a Na+-dependent electrogenic process. Na+ activation of the transport process exhibits sigmoidal kinetics, indicating involvement of more than one Na+ in the activation process. SLC5A8 is silenced in colon cancer in humans, in a mouse model of intestinal/colon cancer, and in colon cancer cell lines. The tumor-associated silencing of SLC5A8 involves DNA methylation by DNA methyltransferase 1. Reexpression of SLC5A8 in colon cancer cells leads to apoptosis but only in the presence of butyrate. SLC5A8-mediated entry of butyrate into cancer cells is associated with inhibition of histone deacetylation. The changes in gene expression in SLC5A8/butyrate-induced apoptosis include upregulation of pro-apoptotic genes and downregulation of anti-apoptotic genes. In addition, the expression of phosphatidylinositol-3-kinase subunits is affected differentially, with downregulation of p85α and upregulation of p55α and p50α.


These studies show that SLC5A8 mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in the colon.

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

Access this article

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

Instant access to the full article PDF.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others


  1. Mortensen PB, Clausen MR. Short-chain fatty acids in the human colon: relation to gastrointestinal health and disease. Scand J Gastroenterol 1996;216:132–148. doi:10.3109/00365529609094568.

    Article  CAS  Google Scholar 

  2. Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol Rev 2001;81:1031–1064.

    PubMed  CAS  Google Scholar 

  3. Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 2001;1:194–202. doi:10.1038/35106079.

    Article  PubMed  CAS  Google Scholar 

  4. Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC. Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol 2005;45:495–528. doi:10.1146/annurev.pharmtox.45.120403.095825.

    Article  PubMed  CAS  Google Scholar 

  5. Miyauchi S, Gopal E, Fei YJ, Ganapathy V. Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na+-coupled transporter for short-chain fatty acids. J Biol Chem 2004;279:13293–13296. doi:10.1074/jbc.C400059200.

    Article  PubMed  CAS  Google Scholar 

  6. Gopal E, Fei YJ, Sugawara M, Miyauchi S, Zhuang L, Martin PM et al. Expression of slc5a8 in kidney and its role in Na+-coupled transport of lactate. J Biol Chem 2004;279:44522–44532. doi:10.1074/jbc.M405365200.

    Article  PubMed  CAS  Google Scholar 

  7. Coady MJ, Chang MH, Charron FM, Plata C, Wallendorff B, Sah J et al. The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter. J Physiol 2004;557:719–731. doi:10.1113/jphysiol.2004.063859.

    Article  PubMed  CAS  Google Scholar 

  8. Paroder V, Spencer SR, Paroder M, Arango D, Schwartz S Jr, Mariadason JM et al. Na+/monocarboxylate transport (SMCT) protein expression correlates with survival in colon cancer: molecular characterization of SMCT. Proc Natl Acad Sci U S A 2006;103:7270–7275. doi:10.1073/pnas.0602365103.

    Article  PubMed  CAS  Google Scholar 

  9. Ganapathy V, Gopal E, Miyauchi S, Prasad PD. Biological functions of SLC5A8, a candidate tumor suppressor. Biochem Soc Trans 2005;33:237–240. doi:10.1042/BST0330237.

    Article  PubMed  CAS  Google Scholar 

  10. Gupta N, Martin PM, Prasad PD, Ganapathy V. SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. Life Sci 2006;78:2419–2425. doi:10.1016/j.lfs.2005.10.028.

    Article  PubMed  CAS  Google Scholar 

  11. Rajendran VM, Binder HJ. Characterization and molecular localization of anion transporters in colonic epithelial cells. Ann N Y Acad Sci 2000;915:15–29.

    Article  PubMed  CAS  Google Scholar 

  12. Sellin JH. SCFAs: the enigma of weak electrolyte transport in the colon. News Physiol Sci 1999;14:58–64.

    PubMed  CAS  Google Scholar 

  13. Gill RK, Saksena S, Alrefai WA, Sarwar Z, Goldstein JL, Carroll RE et al. Expression and membrane localization of MCT isoforms along the length of the human intestine. Am J Physiol Cell Physiol 2005;289:C846–C852. doi:10.1152/ajpcell.00112.2005.

    Article  PubMed  CAS  Google Scholar 

  14. Ritzhaupt A, Wood IS, Ellis A, Hosie KB, Shirazi-Beechey SP. Identification and characterization of a monocarboxylate transporter (MCT1) in pig and human colon: its potential to transport L-lactate as well as butyrate. J Physiol 1998;513:719–732. doi:10.1111/j.1469-7793.1998.719ba.x.

    Article  PubMed  CAS  Google Scholar 

  15. Garcia CK, Goldstein JL, Pathak RK, Anderson RG, Brown MS. Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle. Cell 1994;76:865–873. doi:10.1016/0092-8674(94)90361-1.

    Article  PubMed  CAS  Google Scholar 

  16. Iwanaga T, Takebe K, Kato I, Karaki S, Kuwahara A. Cellular expression of monocarboxylate transporters (MCT) in the digestive tract of the mouse, rat, and humans, with special reference to slc5a8. Biomed Res 2006;27:243–254. doi:10.2220/biomedres.27.243.

    Article  PubMed  CAS  Google Scholar 

  17. Takebe K, Nio J, Morimatsu M, Karaki S, Kuwahara A, Kato I et al. Histochemical demonstration of a Na+-coupled transporter for short-chain fatty acids (slc5a8) in the intestine and kidney of the mouse. Biomed Res 2005;26:213–221. doi:10.2220/biomedres.26.213.

    Article  PubMed  CAS  Google Scholar 

  18. Gopal E, Miyauchi S, Martin PM, Ananth S, Roon P, Smith SB et al. Transport of nicotinate and structurally related compounds by human SMCT1 (SLC5A8) and its relevance to drug transport in the mammalian intestinal tract. Pharm Res 2007;24:575–584. doi:10.1007/s11095-006-9176-1.

    Article  PubMed  CAS  Google Scholar 

  19. Li H, Myeroff L, Smiraglia D, Romero MF, Pretlow TP, Kasturi L et al. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci U S A 2003;100:8412–8417. doi:10.1073/pnas.1430846100.

    Article  PubMed  CAS  Google Scholar 

  20. Gupta N, Miyauchi S, Martindale RG, Herdman AV, Podolsky R, Miyake K, Mager S, Prasad PD, Ganapathy ME, Ganapathy V. Upregulation of the amino acid transporter ATB0,+ (SLC6A14) in colorectal cancer and metastasis in humans. Biochim Biophys Acta 2005;1741:215–223.

    PubMed  CAS  Google Scholar 

  21. Thangaraju M, Gopal E, Martin PM, Ananth S, Smith SB, Prasad PD et al. SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases. Cancer Res 2006;66:11560–11564. doi:10.1158/0008-5472.CAN-06-1950.

    Article  PubMed  CAS  Google Scholar 

  22. Lee BH, Yegnasubramanian S, Lin X, Nelson WG. Procainamide is a specific inhibitor of DNA methyltransferase 1. J Biol Chem 2005;280:40749–40756. doi:10.1074/jbc.M505593200.

    Article  PubMed  CAS  Google Scholar 

  23. He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT et al. Identification of c-MYC as a target of the APC pathway. Science 1998;281:1509–1512. doi:10.1126/science.281.5382.1509.

    Article  PubMed  CAS  Google Scholar 

  24. van de Watering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A et al. The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 2002;111:241–250. doi:10.1016/S0092-8674(02)01014-0.

    Article  Google Scholar 

  25. Canani RB, Terrin G, Cirillo P, Castaldo G, Salvatore F, Cardillo G et al. Butyrate as an effective treatment of congenital chloride diarrhea. Gastroenterology 2004;127:630–634. doi:10.1053/j.gastro.2004.03.071.

    Article  PubMed  Google Scholar 

  26. Rabbani GH, Albert MJ, Rahman H, Chowdhury AK. Short-chain fatty acids inhibit fluid and electrolyte loss induced by cholera toxin in proximal colon of rabbit in vivo. Dig Dis Sci 1999;44:1547–1553. doi:10.1023/A:1026650624193.

    Article  PubMed  CAS  Google Scholar 

  27. Dagher PC, Egnor RW, Taglietta-Kohlbrecher A, Charney AN. Short-chain fatty acids inhibit cAMP-mediated chloride secretion in rat colon. Am J Physiol 1996;27:C1853–C1860.

    Google Scholar 

  28. Vidyasagar S, Barmeyer C, Geibel J, Binder HJ, Rajendran VM. Role of short-chain fatty acids in colonic HCO3 secretion. Am J Physiol 2005;288:G1217–G1226.

    CAS  Google Scholar 

  29. Field M. Intestinal ion transport and pathophysiology of diarrhea. J Clin Invest 2003;111:931–943.

    PubMed  CAS  Google Scholar 

  30. Ganguly NK, Kaur T. Mechanism of action of cholera toxin and other toxins. Indian J Med Res 1996;104:28–37.

    PubMed  CAS  Google Scholar 

  31. Guerrant RL, Carneiro-Filho BA, Dillingham RA. Cholera, diarrhea, and oral rehydration therapy: triumph and indictment. Clin Infect Dis 2003;37:398–405. doi:10.1086/376619.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Vadivel Ganapathy.

Additional information


Stephen A. McClave, M.D. (Louisville, KY): We had this collective knowledge that butyrate is the ultimate food for the colonic epithelium. It has the ultimate trophic effect on cell proliferation and health of the colon. It is interesting to me that the work of Cresci, Ganapathy and others, as they have teased apart the mechanism of this butyrate transport, have led to four clinical applications of this butyrate transporter.

In critical illness, we are adding inulin and fructooligosaccharides and prebiotic fiber to enteral formulas. By stimulating the butyrate transporter, we are downregulating or inhibiting NFkB expression, which downregulates inflammation and reduces oxidative stress. In the ICU that means fewer complications. For patients with severe short bowel syndrome on TPN, dietary fiber facilitates colonic salvage by transporting butyrate across the colonic epithelium. Patients can thus salvage up to 500 calories a day, which can make the difference in gut autonomy and whether or not they get off TPN. In chronic diarrheal diseases in third world countries, adding rice to oral rehydration solutions takes advantage of the sodium transport that is tacked on to the butyrate absorption in the colonic epithelium. In other words, the oral rehydration solution targets small bowel, glucose, and sodium mediated pumps. By adding the rice, we bring in the butyrate transporters and the colon gets further sodium absorption and the diarrhea management gets even easier. And then the fourth and probably most exciting application is what Dr. Cresci is talking about in colonic adenocarcinoma, that the tumor has this uncanny ability to protect itself by turning off the appropriate immune mechanisms that otherwise get rid of the cancer. Furthermore, as we understand the intricacies of this butyrate transporter, that may give us the opportunity in the future to turn this transporter back on and eradicate the cancer.

These investigators are to be applauded for the sophistication of this work, and I anticipate that the results of your efforts are going to go directly to the bedside.

I have one question for you. Listening to your talk, inhibiting or allowing methylation to occur, expressing or not expressing this transporter, I get the impression we have got a light switch on the wall: we can either turn the transporter on or turn it off to protect against cancer. With that in mind, how do we explain the difference between a lifelong history of high fiber in the diet that seems to protect against cancer compared to a 50 year old that gets a big polyp taken out and then goes on four years of fiber, yet sees no benefit?

Gail Cresci, M.S., R.D. (Augusta, GA): Thank you, Dr. McClave, for your great comments, and that is a great question. We have actually done some further studies in the lab where we are looking at normal versus germ free mice, and we have looked for expression of the transporter there, and we see silencing of the transporter in the germ free mice. We are in the process of re colonizing those mice to see if the transporter expression returns, and early stage results have shown that it does return. So I am not sure if it takes a little bit more time than just a quick turn on and turn off switch.

We also know that tumor cells lose their polarity, and so if they lose their polarity, then these transformed cells in the colon don't have access to the luminal butyrate, and it may be that in that case, the dietary fiber in the lumen may not be effective and perhaps other substrates for the transporter, such as pyruvate, which would be more involved in the plasma, may be a better means to affect these tumors.

Thank you very much.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thangaraju, M., Cresci, G., Itagaki, S. et al. Sodium-Coupled Transport of the Short Chain Fatty Acid Butyrate by SLC5A8 and Its Relevance to Colon Cancer. J Gastrointest Surg 12, 1773–1782 (2008).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: