Abstract
Creeping fat (CF) in Crohn's disease (CD) is characterized by hyperplastic mesenteric adipose tissue (MAT) encasing fibrotic intestinal segments. CF exhibits disruptions in microbiota and lipid metabolism, particularly in lysophospholipids (LPC). This study aims to elucidate the impact of LPC on adipogenic differentiation of mesenchymal stem cells in CF and its effects on immune defense functions in the differentiated adipocytes. Isolated adipocytes of MAT from CD and Non-CD patients were analyzed for bacterial counts and composition using AQ-PCR and 16S rRNA. RNA sequencing was performed on isolated adipocytes to assess functionality. LPC levels in CD patients and their effects on adipocyte immune defense were measured using lipidomics, ELISA, and bacterial killing assays. A TNBS-induced colitis model was used to measure LPC levels in plasma and gene expression in MAT. Significant shifts in microbial diversity and bacterial load were observed in CF-derived adipocytes, characterized by increased colonization by pathogenic bacteria and diminished antibacterial capabilities. Sequencing analysis revealed downregulation of antimicrobial genes, including SAA1/2, and upregulation of lipid metabolism-related genes. Lipidomic analysis of CF showed elevated LPC levels, a pro-inflammatory lipid also found in plasma of CD patients. In vitro experiments demonstrated LPC promotes adipogenesis through EGR2, while impairing adipocytes' antibacterial immunity. These findings were consistent in the TNBS-treated mouse model, where increased LPC levels in the blood, and a significant reduction in SAA1/2-positive adipocytes were noted. LPC-induced aberrant adipogenesis in CF is a newly identified pathological feature in CD patients and a potential therapeutic target.
Published Version
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