DIFFERENTIAL EPITHELIAL TRANSPORT OF SHORT-CHAIN FATTY ACIDS UNDER LPS-INDUCED INFLAMMATION: OPPORTUNITIES FOR GUT–BRAIN SIGNALING

Neurodegenerative disorders remain a major unmet challenge, underscoring the need for novel neuroprotective agents. Butyrate, a classical linear microbiota-derived short-chain fatty acid (SCFA), is a well-established modulator of brain function with characterized epithelial transport properties. Its effects are mediated through histone deacetylase inhibition and G-protein-coupled receptor signaling. In contrast, branched-chain fatty acids (BCFAs), including isovaleric acid (IVA), remain understudied despite comparable signaling capacity. Here, we compared the epithelial apparent permeability (P_app) of butyrate and IVA under lipopolysaccharide (LPS)-induced inflammation in vitro. Caco-2 monolayers grown on semipermeable inserts were treated with LPS (500 ng/ml, 24 h) on day 9 of differentiation. On day 10, transepithelial electrical resistance (TEER) was measured, followed by permeability assays for IVA (1–50 mM) and butyrate (1–33 mM) under control and LPS-treated conditions. Samples were derivatized and quantified using LC-MS/MS. LPS significantly reduced TEER (p<0.01), indicating partial barrier disruption, while values remained within the required range (150–600 Ω×cm²). Both metabolites exhibited high permeability (P_app>10*10^-6 cm/s) with >80% recovery. At low concentrations, Papp values were comparable in all cases. Increasing concentrations reduced butyrate permeability in both control and LPS-treated cells. In contrast, IVA permeability remained stable under control conditions and increased following LPS exposure. These findings suggest that butyrate transport predominantly depends on inflammation-sensitive transporters, whereas IVA diffuses passively, maintaining more stable epithelial permeability. This positions IVA as an alternative mediator of gut–brain signaling during neuroinflammation.