P0164 Lauric Acid in Inflammatory Bowel Disease: Balancing Fibrosis Modulation and epithelial-mesenchymal transition Activation
Authors: Patel J , Cejudo-Garcés A , Jarén A , Macias-Ceja D C , López A , Manresa M , Calatayud S , Barrachina M D , Cosin-Roger J , Ortiz-Masiá D 
Published: January 2025

Abstract

Background
Metabolomics has recently emerged as a valuable tool for understanding inflammatory bowel disease (IBD), revealing distinct metabolic profiles for ulcerative colitis (UC) and Crohn’s disease (CD). Lauric acid (LA), a medium-chain fatty acid with anti-inflammatory properties, has an unclear role in IBD, particularly within a fibrotic context. LA interacts with G protein-coupled receptor 84 (GPR84), which is notably elevated in UC1.

Methods
We evaluated the effects of LA (0, 50, 100, and 250 µM) on human intestinal fibroblasts (HSIF) and colonic epithelial cells (CoEpi) under basal and pro-fibrotic (TGFβ1 10 ng/ml) conditions. Fibrotic markers were analyzed using PCR (HSIF: COLA1A, COL3A1, COL4A1, ACTA2, FN1, TGFβ, GPR84; CoEpi: SNAI1/2, CDH1, COLA1A, FNCD4, VIM, GPR84) and Western blot (HSIF: GPR84). Data, expressed as fold induction (mean ± SEM) relative to 0 µM LA, were analyzed using either parametric or non-parametric ANOVA (Kruskal-Wallis) based on normality testing (*P &lt; 0.05 vs. 0 nM LA, **P &lt; 0.01 vs. 0 µM LA, #P &lt; 0.05 vs. 0 µM LA + TGFβ1, ##P &lt; 0.05 vs. 0 µM LA + TGFβ1).

Results
Under basal conditions, LA significantly reduced mRNA expression of collagen molecules [COL1A1 (250 µM: 0.2 ± 0.07**) and COL3A1 (50 µM: 0.4 ± 0.1**)] and αSMA [ACTA2 (100 µM: 0.1 ± 0.1**)] in HSIF cells. In pro-fibrotic conditions, LA maintained or enhanced its protective effect, often at lower doses [COL1A1 (50 µM: 1.1 ± 0.15##), COL3A1 (50 µM: 0.24 ± 0.1#), COL4A1 (250 µM: 0.6 ± 0.1#), ACTA2 (100 µM: 0.7 ± 0.4#)]. LA also increased GPR84 mRNA and protein expression under basal (250 µM: 1167 ± 646*) and pro-fibrotic (250 µM: 1048 ± 505##) conditions, with no changes in fibronectin or TGF expression in HSIF cells. In CoEpi cells, LA promoted epithelial-mesenchymal transition (EMT) under both conditions, shown by changes in mRNA for VIMENTIN (250 µM: 3.9 ± 0.6*; 250 µM + TGFβ1: 6.4 ± 1.5#), SNAI2 (250 µM: 3.4 ± 0.5*; 250 µM + TGFβ1: 3.9 ± 0.5##), E-CADHERIN (250 µM: 0.5 ± 0.08*; 250 µM + TGFβ1: 0.3 ± 0.07#), and FIBRONECTIN (250 µM: 2.6 ± 0.5*; 250 µM + TGFβ1: 4.4 ± 0.8##). GPR84 mRNA was significantly elevated by LA in basal (250 µM: 6.9 ± 1.5**) and pro-fibrotic (250 µM: 5.1 ± 1.0##) conditions. No changes were observed for COLA1A or SNAI1 expression in CoEpi cells.

Conclusion
LA exhibits a dual role in colonic epithelial and fibroblast cells, showing context-dependent effects that can offer therapeutic benefits or pose challenges. Its interaction with GPR84 underscores a complex regulatory function that requires further study.

References
Bauset C, Carda-Diéguez M, Cejudo-Garcés A, Buetas E, Seco-Cervera M, Macias-Ceja DC, Navarro-Vicente F, Esplugues JV, Calatayud S, Mira Á, Ortiz-Masiá D, Barrachina MD, Cosín-Roger J. A disturbed metabolite-GPCR axis is associated with microbial dysbiosis in IBD patients: Potential role of GPR109A in macrophages. Biochim Biophys Acta Mol Basis Dis. 2024 Dec;1870(8):167489. doi: 10.1016/j.bbadis.2024.167489. Epub 2024 Sep 2. PMID: 39233260.