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

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, AChinduced 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.

Oleanolic acid ameliorates intestinal alterations associated with EAE

“…1 f and Figure S2 A and B). Since iso-valeric acid has been related to colon smooth muscle cell relaxation [ 24 ], we considered the study of this microbial metabolite in intestinal epithelium, through the different in vitro responses. Further in this line, motilin, an important protein associated with gastrointestinal motility, was also quantified (Fig.…”

“…Depressive symptoms and depressive-like behavior are frequently perceived in both patients and experimental models of MS [ 39 , 40 ]. Moreover, iso-valeric acid has also been found to block motility of colon smooth muscle cells [ 24 ], therefore directly contributing to constipation, one of the clinical signs in EAE and MS. Since we found IL-8 upon stimulation of colon epithelial cells with iso-valeric acid, this SCFA could contribute to the inflammatory environment of EAE, deserving further investigation.…”

Preliminary evaluation of fecal fatty acid concentrations in cats with chronic kidney disease and correlation with indoxyl sulfate and p‐cresol sulfate

“…Although straight‐chain SCFAs, primarily butyrate and propionate, have been shown to have a prokinetic effect by promoting contraction of smooth muscle in the colon in ex vivo studies evaluated in colonic tissue from dogs, cats, and guinea pigs, BCFAs and other products of protein fermentation in the colon are considered deleterious to the gut. For example, isovaleric acid has been shown to cause colonic smooth muscle relaxation in an ex vivo rodent model . In addition, decreased gastrointestinal motility has been linked directly to uremia by causing dysbiosis and colonic inflammation secondary to increased uremic toxin exposure in rodent models .…”

“…In contrast, BCFAs represent only a small portion (5%) of total SCFA production and are produced when protein passes through the small intestine unabsorbed and protein‐derived branched chain amino acids are fermented by microbiota in the colon . Branched‐chain SCFAs and other products of protein fermentation in the colon are considered deleterious to the gut and may promote inflammation as well as have negative effects on motility in a rodent model …”

Isovaleric acid ameliorates ovariectomy‐induced osteoporosis by inhibiting osteoclast differentiation

“…16,17 Previous reports showed that BCFAs affect energy metabolism and cause colon smooth muscle relaxation. 18,19 Another report demonstrated that enterochromaffin cells are activated by a microbial metabolite, IVA, via Olfr558. 20 However, much remains unknown regarding whether BCFAs regulate additional cellular activities and differentiation.…”