Physiological concentrations of short-chain fatty acids immediately suppress colonic epithelial permeability

Abstract

Colonic fermentation products, SCFA, have various effects on colonic functions. Here, we found that physiological concentrations of SCFA immediately promote epithelial barrier function in the large intestine. Solutions of mixed and individual SCFA were applied to the caecal walls mounted on Ussing-type chambers. Transepithelial electrical resistance (TER) increased rapidly and reached a peak 35 % higher than that in the control specimen within 10 min post application of the SCFA mixture (80 acetate, 40 propionate, 20 butyrate (mmol/l)). The Lucifer yellow permeability, a paracellular transport marker, was dose-dependently reduced by the mixed SCFA, acetate and propionate solutions. Inhibition of monocarboxylate transporter-1 did not influence the increase in TER with acetate; however, lowering the pH (from 7·5 to 5·5) clearly enhanced the effect of acetate. Non-metabolizable, bromo and chloro derivatives of SCFA also increased TER. These results suggest that passive diffusion of SCFA is dominant and the metabolism of SCFA is not required for the promotive effect of SCFA on barrier function. We also observed that individual SCFA dose-dependently increased TER in T84 and Caco-2 cells, which indicates that SCFA directly stimulate epithelial cells. Depletion of membrane cholesterol and inhibitors of phosphatidylinositol-3 kinase and Gq protein attenuated the acetate-mediated promotive effect. Finally, we found that the mucosal application of the SCFA mixture dose-dependently suppressed [ 3 H] mannitol transport from the caecal lumen to the mesenteric blood in the anaesthetized rats. We conclude that physiological concentrations of SCFA immediately enhance barrier function of the colonic epithelium through cholesterol-rich microdomain in the plasma membrane.

Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome

“…SCFAs such as acetate promote gut epithelial integrity 14,21 . An indication as to the molecular pathways used by SCFAs was suggested through the use of inhibitors of GPCR signalling 21 .…”

“…SCFAs such as acetate promote gut epithelial integrity 14,21 . An indication as to the molecular pathways used by SCFAs was suggested through the use of inhibitors of GPCR signalling 21 . We therefore determined whether the beneficial effects of fibre on DSS colitis were mediated via the metabolitesensing GPCRs GPR43 (also referred to as FFA2) and GPR109A (also referred to as HCA2).…”

“…Currently, the inflammasome pathway and production of the cytokine IL-18 are the best-characterized molecular mechanisms for maintenance of epithelial integrity, repair and intestinal homeostasis [15][16][17][18] . Since dietary fibre as well as SCFAs are known contributors to epithelial integrity 14,21,24 , we examined the influence of diet and the SCFA receptors GPR43 on inflammasome activation and IL-18 production. Western blots of colonic epithelial cells following DSS colitis showed that zerofibre feeding yielded very low to absent levels of the cleaved form of caspase 1 ( Fig.…”

Gleaning Insights from Fecal Microbiota Transplantation and Probiotic Studies for the Rational Design of Combination Microbial Therapies

“…These transmembrane components interact with plaque proteins, including zonula occludens (ZO) family members (180), in order to mediate intracellular signaling and cytoskeletal reorganization (181,182). The expression of tight junction molecules in the healthy gut is modulated by numerous environmental signals, including metabolic compounds such as acetate and short-chain fatty acids (SCFAs) (183), although the exact mechanisms by which this occurs are still unclear. Some studies suggest that butyrate, an SCFA whose level increases with probiotic administration, decreases intestinal permeability through the induction of AMP-activated protein kinase activity and the increased assembly of tight junctions in Caco-2 monolayers (184).…”

Short-chain fatty acid receptor GPR43 is expressed in canine enteroendocrine L cells

“…Apart from being absorbed as nutrients across the intestine, SCFA influence various physiological processes in the intestinal tract including intestinal motility, colonic barrier function, and secretion of the gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) (1)(2)(3) . Both hormones are involved the regulation of digestive functioning and appetite (4) .…”