Líf - og heilbrigðisvísindaráðstefna Háskóla Íslands 2023

Effects of novel macrolide compounds on barrier enhancement in colon epithelium

Ragnheiður Olga Jónsdóttir, Hildur Rún Helgudóttir, Jón Pétur Jóelsson, Þórarinn Guðjónsson, Jennifer Kricker

Introduction: Inflammatory bowel diseases (IBD) are complex inflammatory conditions of the colon and small intestine, with Crohn´s disease and ulcerative colitis being the two main types. Current treatments include immunomodulators and corticosteroids that treat symptoms, but neither the cause nor the compromised intestinal epithelial barrier that plays a critical role in the pathophysiology. As the antibiotic macrolide azithromycin (AZM) has been shown to have barrier-enhancing properties separate from its antibiotic properties, EpiEndo Pharmaceuticals has developed non-antibiotic derivatives of AZM, termed barriolides. Methodology: In this project, we have used human colon epithelial lines to evaluate the effects of the barriolides on the gut epithelium. Cells were cultured in air-liquid and liquid-liquid cultures, and the epithelial barrier was analysed by measuring transepithelial electrical resistance (TEER). A colitis-like condition was induced by treating cells with a mixture of inflammatory cytokines. Cell responses were examined using gene expression analysis, phospholipid accumulation, viability and proliferation studies, and immunostainings. Results: Of 15 compounds tested, 12 did not affect cell proliferation and viability. The compounds were then screened for barrier-enhancing properties. Six compounds increased TEER and showed an accumulation of phospholipids in the cells. H&E stainings on cell monolayers treated with the compounds also showed enlarged cells compared to untreated cells. Conclusion: Barriolides are a novel class of drugs with epithelial barrier-enhancing properties. Six show promising effects in enhancing the gut epithelial barrier in culture. Further studies aim to test these compounds on an organ-on-chip assay and evaluate the molecular mechanisms behind the barrier-enhancing effects.


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