The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 17 No. 5 • June 2014

The Short Chain Fatty Acid Butyrate Activates the Niacin Receptor GPR109A

The Anti-Atherosclerotic Plot Thickens: Niacin and Dietary Fiber for “Clean” Arteries

The short chain fatty acid butyrate (produced by certain microbes in the lower digestive tract from indigestible fermentable fiber that reaches the colon) and the vitamin niacin (nicotinic acid, vitamin B3) both act as ligands for (activating) the GPR109A receptor.1,2 This surprising link has resulted in both additional understanding of how niacin works and what butyrate does, but also introduces additional questions concerning how this all adds up, as not that much is known about GPR109A or how niacin works.

A recent paper3 explains that in a mouse model lacking the GPR109A receptor, the anti-lipolytic effect of niacin (inhibition of enzymatic release of free fatty acids) is blocked—but this didn’t have an effect on the usual beneficial changes in plasma LDL and HDL levels produced by high-dose niacin. Thus, niacin’s effects on LDL and HDL are not linked to GPR109A, but its antilipolytic effect is. Meanwhile, the tumor-suppressive effects of butyrate in the colon were found to be mediated by butyrate acting as a ligand at the GPR109A receptor.2 As the authors2 explain, the circulating level of butyrate (about 5 μmol/L) is not high enough to activate the GPR109A receptor, but in the colon, butyrate levels are much higher (about 20 mmol/L) and, at that concentration, able to activate the receptor. Thus, the researchers conclude that, “GPR109A mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in colon.”

Niacin was proposed to reduce the progression of atherosclerosis independently of its lipid-modifying effects through GPR109A mediated antiinflammatory effects in immune cells.1 In one paper,4 human monocytes were pretreated with niacin and then activated by the addition of the Toll-like receptor 4 immune stimulant bacterial lipopolysaccharide. Determination of the resulting secretion of proinflammatory mediators revealed that niacin reduced the secretion of TNF-alpha by 49.2 ± 4.5%, reduced IL-6 by 56.2 ± 2.8%, and reduced monocyte chemoattractant protein 1 by 59.3 ± 5.3%. Interestingly, inhibition of prostaglandin D2 receptor (activation of which causes niacin flushing) did not alter the antiinflammatory effects of niacin described here. This may mean that preventing niacin flushing won’t interfere with niacin’s antiinflammatory effects, but doesn’t tell us whether preventing niacin flushing would interfere with niacin’s effects on HDL and LDL. “The jury is still out” on whether it is a good idea to interfere with niacin flushing. See the June 2009 issue of this newsletter for a speculative article we wrote on the niacin flush.

Colon cancer is reported to be able to silence GPR109A by increasing DNA methylation at that receptor, but the expression of GPR109A can be restored in the presence of butyrate and niacin.2

We wonder about the possibility of an additive antilipolytic effect of butyrate and niacin in the general circulation. Although the concentration of butyrate is much too low (about 4000 times too low in the general circulation) to activate GPR109A by itself, it would be interesting to determine whether it might add anything to the antilipolytic effect of niacin. As powerful anti-inflammatory effects of niacin in monocytes have been identified recently as mediated by GR109A, and as butyrate is a ligand of GPR109A (at least at its concentration in the colon), the combination could be very potent in reducing the risk of colon cancer and inflammatory conditions in the lower digestive tract.4

Conspicuously absent from these data and from the analysis of anti-atherosclerotic mechanisms resulting from fermentation of indigestible fiber reaching the lower digestive tract is the large amounts of hydrogen that can be produced by gut microbes in residence there. Whether the presence of all that hydrogen is additive with or synergistic with the anti-atherosclerotic properties of the short chain fatty acids, if it is, remains to be explained.


  1. Lukasova et al. Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. J Clin Invest. 1213:1163-73 (2011).
  2. Thangaraju et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 69(7):2826-32 (Apr. 1, 2009).
  3. Lauring et al. Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression. Sci Transl Med. 4(148):148ra115 (2012).
  4. Digby et al. Anti-inflammatory effects of nicotinic acid in human monocytes are mediated by GPR109A dependent mechanisms. Arterioscler Thromb Vasc Biol. 32(3):669-76 (2012).

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