Decanoic acid in Crohn's disease-associated complications: Antifibrotic effect mediated by PPARγ.

Abstract

Crohn's disease (CD) is frequently complicated by stricturing and penetrating manifestations driven by intestinal fibrosis, for which reliable biomarkers and effective antifibrotic therapies are lacking. Metabolic alterations have emerged as potential modulators of disease behavior. Here, we investigated the clinical relevance and mechanistic role of the medium-chain fatty acid decanoic acid in CD-associated complications. Plasma decanoic acid levels were quantified by LC-HRMS in CD patients and analyzed according to disease activity and behavior. Receiver operating characteristic (ROC) curves were used to evaluate discriminatory capacity. Functional effects were assessed in acute and chronic dextran sulfate sodium (DSS)-colitis models. Inflammation and fibrosis were evaluated by histological, immunohistochemical, and molecular analyses. Mechanistic studies were performed in human small intestinal fibroblasts (HSIFs) using pharmacological inhibition and siRNA-silencing of GPR84 and PPARγ. Circulating decanoic acid levels were significantly reduced in active and complicated-CD patients and it accurately discriminated active from in remission (AUC=0.7212) and complicated from non-complicated patients (AUC = 0.8403). Oral administration of decanoic acid ameliorated disease severity in acute and chronic colitis, reduced pro-inflammatory mediators, and markedly attenuated intestinal fibrosis, as evidenced by decreased collagen deposition and profibrotic gene expression. In vitro, decanoic acid directly suppressed fibroblast activation and extracellular matrix production through PPARγ, but not GPR84. Our study identifies reduced circulating decanoic acid as a metabolic signature of complicated CD and demonstrates its anti-inflammatory and antifibrotic properties through PPARγ. Decanoic acid may represent both a biomarker of disease activity and behavior and a potential therapeutic adjunct to target intestinal fibrosis in CD.