World Immune Regulation Meeting XVIII 2024, Chur, Switzerland, 13 – 16 March 2024, vol.18, no.38, pp.45
Pat Y., Yazici D., Öğülür İ., Ardıçlı S., Simmons S., Almada A., Avena C., Jensen T., Li M., Zhu X., Bu X., Mitamura Y., Heider A., Babayev H., Dhir R., Zhang L., Akdiş M., Nadeau K., Akdiş C.
Abstract
The gut microbiota protects the gastrointestinal system’s homeostasis by producing antimicrobial substances, vitamins and metabolites, strengthening the gut epithelial barrier, inhibiting opportunistic pathogen colonization and regulating the immune system. In addition, the gut microbiome has prominent roles in skin epithelial homeostasis (gut-skin axis), which can be seen in inflammatory skin diseases such as atopic dermatitis. We identified a gut microbiome metabolite, (here named compound X) which improves gut epithelial barrier development speed and integrity as demonstrated in gut-on-a-chip 3D cultures. The surface application of 0.25, 1- and 4-mM doses of compound X significantly increases the gut epithelial barrier integrity compared to control by almost 2 times up to 800 ohm x cm2 during the gut development phase of the gut epithelial barrier. The transcriptomic analysis shows that it upregulates gene expression associated with xenobiotics metabolism, ion transport, water transport, glucose transport, and amino acid transport pathways. It increases the tight junction protein claudin-1 gene expression. It shows an anti-inflammatory activity, as demonstrated with decreased chemokines (CXCL-5,10 and 11, CCL-20,23 and 25, CSF-1 and MCP-1) and IL-1a levels in culture medium detected by proximity extension assay. Untargeted proteomics analysis revealed that 4 mM compound X upregulates glycolysis, tricarboxylic acid cycle and oxidative phosphorylation and downregulates lipid metabolism pathways-related proteins. Next, we assessed its effect 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 uM) alone rescued the surfactant, cocoyl methyl glucamide-induced skin epithelial barrier damage within 24 hours. In addition, it reversed the inflammation caused by cocoyl methyl glucamide demonstrated by decreased IL-18, CSF-1, PRDX-3 and PD-L1 protein levels. In conclusion, our data highlights compound X, a gut microbiome metabolite, as a promising agent for preventing, rescuing and treating gut and skin epithelial barrier impairment.
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