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

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Journal of Gastrointestinal Surgery

Abstract

Introduction

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.

Results

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.

Conclusion

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

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Correspondence to Vadivel Ganapathy.

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Discussion

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.

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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). https://doi.org/10.1007/s11605-008-0573-0

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