Arjunolic acid protects the intestinal epithelial barrier, ameliorating Crohn's disease-like colitis by restoring gut microbiota composition and inactivating TLR4 signalling

Abstract

Background and AimsCrohn's disease (CD) is characterized by an overabundance of epithelial cell death and an imbalance in microflora, both of which contribute to the dysfunction of the intestinal barrier. Arjunolic acid (AA) has anti-apoptotic effects and regulates microbiota efficacy. The objective of this study was to assess the impact of the treatment on colitis resembling Crohn's disease, along with exploring the potential underlying mechanism. MethodsCD animal models were created using Il-10−/− mice, and the impact of AA on colitis in mice was evaluated through disease activity index, weight fluctuations, pathological examination, and assessment of intestinal barrier function. To clarify the direct role of AA on intestinal epithelial cell apoptosis, organoids were induced by LPS, and TUNEL staining was performed. To investigate the potential mechanisms of AA in protecting the intestinal barrier, various methods including bioinformatics analysis and FMT experiments were employed. ResultsThe treatment for AA enhanced the condition of colitis and the function of the intestinal barrier in Il-10−/− mice. This was demonstrated by the amelioration of weight loss, reduction in tissue inflammation score, and improvement in intestinal permeability. Moreover, AA suppressed the apoptosis of intestinal epithelial cells in Il-10−/− mice and LPS-induced colon organoids, while also reducing the levels of Bax and C-caspase-3. In terms of mechanism, AA suppressed the activation of TLR4 signaling in Il-10−/− mice and colon organoids induced by LPS. In addition, AA increased the abundance of short-chain fatty acid-producing bacteria in the stool of Il-10−/- mice, and transplantation of feces from AA-treated mice improved CD-like colitis. ConclusionsThe results of our study demonstrate that AA has a protective effect on the intestinal barrier in Crohn's disease-like colitis by preventing apoptosis. Additionally, this groundbreaking study reveals the capacity of AA to hinder TLR4 signaling and alter the makeup of the intestinal microbiome. The findings present fresh possibilities for treating individuals diagnosed with Crohn's disease. AA offers a hopeful novel strategy for managing Crohn's disease by obstructing crucial pathways implicated in intestinal inflammation and enhancing the gut microbiota.