Valeric Acid in IBD

Background & Aims: Valeric acid (VA) is a microbially produced short-chain fatty acid (SCFA). While emerging evidence suggests anti-inflammatory potential, the epithelial-specific effects of VA under inflammatory conditions in inflammatory bowel disease (IBD) remain poorly defined. We aimed to investigate the concentration- and context-dependent effects of VA on human colonic epithelium and to explore potential mechanisms. Methods: Primary human colonic organoids derived from three donors were subjected to cytokine-induced inflammation (TNF-a, IL-1ß, IFN-?) and treated with increasing concentrations of VA (0–10 mM) for 6 or 24 hours, with or without a 1-hour pre-treatment. Transcriptomic profiling was performed, and data were analyzed using multifactorial linear models, pathway enrichment, and inflammation/barrier composite scores. Selected findings were validated against human colonic biopsy transcriptomes from IBD patients and controls (n=536). In parallel, barrier function was assessed by transepithelial electrical resistance (TEER) using the ECIS® system in T84 epithelial monolayers. Results: VA attenuated cytokine-induced inflammatory transcriptional programs in a dose-dependent manner, including downregulation of inflammatory pathways (TNF, JAK-STAT, NOD-like receptor signaling), oxidative stress mediators NOS2 (iNOS) and DUOX2, and suppression of biopsy-based molecular inflammation gene sets. TEER assay demonstrated that VA at 1 mM did not alter barrier resistance, whereas prolonged exposure to 3 mM VA induced a modest but significant reduction in barrier integrity, indicating a late, dose-dependent detrimental effect. Consistently, transcriptomic analysis revealed impaired epithelial barrier-associated gene expression, including TJP1, TJP2, and FUT2. At the molecular level, VA modulated multiple histone deacetylases (HDACs) in a non-uniform, concentration-dependent manner, independent of classical SCFA receptors or transporters. Conclusions: VA exerts dual effects on the human colonic epithelium, robust anti-inflammatory activity coupled with dose- and time-dependent impairment of barrier function. VA also regulates transcription of multiple histone deacetylases (HDACs) in a concentration-dependent manner. These findings highlight the context- and dose-dependent actions of VA and underscore the need for careful consideration of its therapeutic potential in IBD.