In Vitro and In Vivo Efficacy of Epithelial Barrier-Promoting Barriolides as Potential Therapy for Ulcerative Colitis

<b>Background/Objectives</b>: Ulcerative colitis (UC) is an inflammatory bowel disease and a major cause of ulcers and chronic inflammation in the colon and rectum. Recurring symptoms include abdominal pain, rectal bleeding, and diarrhoea, and patients with UC are at a higher risk of developing comorbidities such as colorectal cancer and poor mental health. In UC, the decreased diversity and changed metabolic profile of gut microbiota, along with a diminished mucus layer, leads to disruption of the underlying epithelial barrier, with an ensuing excessive and detrimental inflammatory response. Treatment options currently rely on drugs that reduce the inflammation, but less emphasis has been placed on improving the resilience of the epithelial barrier. Macrolide antibiotics exhibit epithelial barrier-enhancing capacities unrelated to their antibacterial properties. <b>Methods</b>: We investigated two novel barriolides, macrolides with reduced antibacterial effects in common bacterial strains. Gut epithelial cell barrier resistance in the Caco-2 cell line, with and without co-culture with mucus-producing HT-29 cells, was increased when treated with barriolides. Using ^AXGut-on-Chip technology with inflammatory cytokine-stimulated Caco-2/HT-29 co-cultures, the effectiveness of the barriolides was confirmed. Lastly, we reveal the barrier-enhancing and inflammation-reducing effects of the barriolides in a dextran-sulphate sodium (DSS)-induced colitis mouse model. <b>Results</b>: We show the predictive power of the novel ^AXGut-on-Chip system and the effectiveness of the novel barriolides. Indications include reduced inflammatory response, increased epithelial barrier and decreased overall clinical score. <b>Conclusions</b>: The results of this study indicate the notion that barriolides could be used as a treatment option for UC.