Slc5a8, a Na+-coupled high-affinity transporter for short-chain fatty acids, is a conditional tumour suppressor in colon that protects against colitis and colon cancer under low-fibre dietary conditions

Abstract

Summary Mammalian colon harbors trillions of bacteria under physiologic conditions; this symbiosis is made possible because of a tolerized response from the mucosal immune system. The mechanisms underlying this tolerogenic phenomenon remain poorly understood. Here we show that Slc5a8, a Na+-coupled high-affinity transporter in colon for the bacterial fermentation product butyrate, plays a critical role in this process. Among various immune cells in colon, dendritic cells (DCs) are unique not only in their accessibility to luminal contents but also in their ability to induce tolerogenic phenotype in T cells. We found that DCs exposed to butyrate express the immunosuppressive enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and aldehyde dehydrogenase 1A2 (Aldh1A2), promote conversion of naïve T cells into immunosuppressive FoxP3+ Tregs, and suppress conversion of naïve T cells into pro-inflammatory IFN-γ-producing cells. Slc5a8-null DCs do not induce IDO1 and Aldh1A2 and do not generate Tregs or suppress IFN-γ-producing T cells in response to butyrate. We also provide in vivo evidence for an obligatory role for Slc5a8 in suppression of IFN-γ-producing T cells. Furthermore, Slc5a8 protects against colitis and colon cancer under conditions of low-fiber intake but not when dietary fiber intake is optimal. This agrees with the high-affinity nature of the transporter to mediate butyrate entry into cells. We conclude that Slc5a8 is an obligatory link between dietary fiber and mucosal immune system via the bacterial metabolite butyrate, and that this transporter is a conditional tumor suppressor in colon linked to dietary fiber content.

SLC transporters as a novel class of tumour suppressors: identity, function and molecular mechanisms

“…Therefore, it is possible that the bacterial fermentation products suppress the development of DCs to impart a tolerogenic phenotype to the mucosal immune system. This indeed seems to be the case [54,55]. Butyrate shows a marked negative effect on DC development from bone marrow progenitor cells.…”

“…With this logic, we repeated the same experiments that Frank et al [52] did, but with two different dietary conditions: high-fibre content (HF-Diet) and low-fibre content (LF-Diet). We examined the progression of dextran sulfate sodium (DSS)-induced colitis and DSS/AOM (azoxymethane)-induced colon cancer in wild-type mice and Slc5a8 −/− mice using these two different dietary conditions [54]. First, we used 2 % DSS to investigate the influence of Slc5a8 on colonic inflammation.…”

“…Colonic epithelial cells as well as DCs in the lamina propria express high levels of IDO1, contributing to the tolerogenic phenotype of the mucosal immune system. Recent studies have shown that Slc5a8 and the bacterial-derived HDAC inhibitors butyrate and propionate are critical for these phenomena in the mucosal immune system [54]. The bacterial metabolites induce IDO1 in wild-type DCs but fail to do so in Slc5a8 −/− DCs.…”

Gut Microbiome and Colon Cancer: Role of Bacterial Metabolites and Their Molecular Targets in the Host

“…Despite the ability of SMCT1 to function as a tumor suppressor in vitro , mice lacking the transporter do not demonstrate a significantly increased risk for cancer [34]. The tumor-suppressive function of the transporter is linked to the fiber content in the diet; even though the knockout mice did not show any difference in cancer risk when fed a diet rich in fiber, the mice exhibited increased cancer risk when fed a diet low in fiber [35**]. This finding appears to be directly linked to the high affinity of SMCT1 for butyrate and propionate, which makes the contribution of the transporter to the total uptake of these HDAC inhibitors in colonic epithelial cells insignificant when these metabolites are present at high concentrations, as in the setting of a high fiber diet.…”

Short, but Smart: SCFAs Train T Cells in the Gut to Fight Autoimmunity in the Brain

“…Bacterial fermentation products, principally short-chain fatty acids (SCFAs), mediate the effects of gut microbes on the host immune system, regulating the differentiation and function of almost every cell type in the immune cell repertoire of the gut. The molecular mechanisms underlying this process involve not only cell-surface receptors such as GPR109A, GPR41, and GPR43 (Ganapathy et al, 2013; Kim et al, 2014) but also intracellular targets such as histone deacetylases (Singh et al, 2010; Gurav et al, 2015). Subsequently it became apparent that the modulation of the mucosal immune system by gut microbes is not limited solely to facilitation of their co-existence with the host; it also has significant impact on colonic health protecting against inflammation and carcinogenesis.…”