Butyrate-Mediated Protection Against Colonic Inflammation And Colon Carcinogenesis: Role Of Butyrate Transporters And Butyrate Receptors

Butyrate is a short-chain fatty acid generated at millimolar concentrations in coloniclumen by bacterial fermentation of dietary fiber. This bacterial metabolite elicits aplethora of biological effects on the host, influencing the function of not only the colonicepithelial cells but also that of the gut-associated immune cells and enteric neurons. In thepast, most of the research on the role of butyrate in colon focused on its ability to inhibithistone deacetylases with consequent changes in gene expression. Recent studies haveexpanded the area of research on butyrate with the identification of specific transportersthat facilitate the entry of butyrate into cells. This includes the low-affinity/high capacitytransporters SLC16A1, SLC16A3 and SLC16A7, and the high-affinity/low-capacitytransporter SLC5A8. These transporters are relevant to the ability of butyrate to inhibithistone deacetylases in colon cells, gut-associated immune cells, and enteric neurons.With optimal fiber intake, the luminal concentrations of butyrate are in the millimolarrange, making the low-affinity transporters more relevant than the high-affinitytransporters in colon cells. When the dietary fiber intake is low, the luminalconcentrations of butyrate decrease, making the high-affinity transporter more relevantthan the low-affinity transporters. The situation is different for the immune cells andneurons, which reside in the lamina propria beneath the epithelial cell layer. These cellsare exposed only to micromolar concentrations of butyrate that cross the epithelialbarrier; therefore, the high-affinity transporter is predominantly responsible for butyrateentry into these cells even when the dietary fiber intake is optimal. Butyrate elicitsprofound influence on mucosal immune cells and enteric neurons, and SLC5A8 is thetransporter relevant to these biological effects of butyrate. The biological effects ofbutyrate are also mediated through three different G-protein-coupled receptors, namelyGPR41, GPR43, and GPR109A. All three receptors are expressed on the apicalmembrane of colonic epithelial or enteroendocrine cells and are activated maximally bybutyrate at concentrations found in the lumen. The signaling pathways associated withthe activation of these receptors profoundly affect the biology of colon cells and mucosalimmune cells. Butyrate provides significant protection against colonic inflammation andcolon cancer, but little was known on the mechanisms responsible for these effects. Thediscovery of specific transporters and cell-surface receptors for butyrate in colon cells,mucosal immune cells, and enteric neurons provides a molecular basis for the beneficialeffects of this bacterial metabolite in colon.