1. Academic Validation
  2. Branched Short-Chain Fatty Acid Isovaleric Acid Causes Colonic Smooth Muscle Relaxation via cAMP/PKA Pathway

Branched Short-Chain Fatty Acid Isovaleric Acid Causes Colonic Smooth Muscle Relaxation via cAMP/PKA Pathway

  • Dig Dis Sci. 2019 May;64(5):1171-1181. doi: 10.1007/s10620-018-5417-5.
Bryan A Blakeney 1 Molly S Crowe 1 Sunila Mahavadi 1 Karnam S Murthy 1 John R Grider 2
Affiliations

Affiliations

  • 1 Department of Physiology and Biophysics, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Box 980551, Richmond, VA, 23298, USA.
  • 2 Department of Physiology and Biophysics, VCU Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Box 980551, Richmond, VA, 23298, USA. john.grider@vcuhealth.org.
Abstract

Background: Isovaleric acid (IVA) is a 5-carbon branched-chain fatty acid present in fermented foods and produced in the colon by Bacterial fermentation of leucine. We previously reported that the shorter, straight-chain fatty acids acetate, propionate and butyrate differentially affect colonic motility; however, the effect of branched-chain fatty acids on gut smooth muscle and motility is unknown.

Aims: To determine the effect of IVA on contractility of colonic smooth muscle.

Methods: Murine colonic segments were placed in a longitudinal orientation in organ baths in Krebs buffer and fastened to force transducers. Segments were contracted with acetylcholine (ACh), and the effects of IVA on ACh-induced contraction were measured in the absence and presence of tetrodotoxin (TTx) or inhibitors of nitric oxide synthase [L-N-nitroarginine (L-NNA)] or Adenylate Cyclase (SQ22536). The effect of IVA on ACh-induced contraction was also measured in isolated muscle cells in the presence or absence of SQ22536 or protein kinase A (PKA) inhibitor (H-89). Direct activation of PKA was measured in isolated muscle cells.

Results: In colonic segments, ACh-induced contraction was inhibited by IVA in a concentration-dependent fashion; the IVA response was not affected by TTx or L-NNA but inhibited by SQ22536. Similarly, in isolated colonic muscle cells, ACh-induced contraction was inhibited by IVA in a concentration-dependent fashion and the effect blocked by SQ22536 and H-89. IVA also increased PKA activity in isolated smooth muscle cells.

Conclusions: The branched-chain fatty acid IVA acts directly on colonic smooth muscle and causes muscle relaxation via the PKA pathway.

Keywords

Adenylyl cyclase; Branched-chain fatty acid; Colon; Cyclic AMP; H-89; Isovaleric acid; L-N-nitroarginine; Nitric oxide synthase; Protein kinase A; SQ22536; Smooth muscle; Tetrodotoxin.

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