Akademik Veri Yönetim Sistemi
EUROPEAN JOURNAL OF IMMUNOLOGY, cilt.54, sa.S1, ss.964, 2024 (SCI-Expanded)
Gut microbiota protects the gastrointestinal system's homeostasis by producing antimicrobial substances, vitamins, and metabolites, which aid in strengthening the gut epithelial barrier, inhibiting opportunistic pathogen colonisation and regulating the immune system. In addition, same bacterial products may have prominent roles in skin barrier homeostasis. With this perspective, we identify a gut microbiome metabolite (compound X) that improves gut epithelial barrier development speed and integrity as demonstrated in gut-on-a-chip Caco-2 3D cultures. The surface application of 0.25, 1- and 4-mM doses of compound X significantly increase the gut epithelial barrier integrity compared to control (P<0.0001) by almost 2 times (Transepithelial Electrical Resistance-TEER), during the gut development phase of the barrier. Transcriptomic analysis shows an upregulation of gene expression associated with xenobiotic metabolism, ion, water, glucose, and amino acid transport pathways. It increases the gene expression of the tight junction protein, claudin-1 and displays anti-inflammatory activity, as demonstrated by decreased chemokines (CXCL5, 10 and 11, CCL20, 23 and 25, CSF-1 and MCP-1) and IL-1 α levels detected by proximity extension assay in media. Untargeted proteomics analysis reveals that compound X upregulates glycolysis, tricarboxylic acid cycle and oxidative phosphorylation and downregulates lipid metabolism pathways-related proteins. A 6-day pretreatment with compound X successfully prevents proinflammatory cytokine (TNF-α, IFN-γ and IL-1β) driven gut epithelial barrier impairment. Next, we assess its effects on skin epithelial barrier integrity with an ex vivo skin tissue model. Treatment of systemic circulation-relevant doses of compound X (0.25,1 and 4 μM) rescues surfactant (cocoyl methyl glucamide; CMG)-induced skin epithelial barrier damage within 24 hours. In addition, it reverses the inflammation caused by CMG, as demonstrated by decreased IL-18, CSF-1, PRDX-3 and PD-L1 protein levels. In conclusion, our data highlights compound X, as a promising agent for preventing, rescuing, and treating gut and skin epithelial barrier impairment. Studies are going on to confirm the associated pathways mechanistically by using CRISPR/Cas9 in human intestinal organoids and to check the mitigation effect of compound X on surfactant-treated skin of mice in vivo.