PPAR-Gamma coordinates EMT, AGE, and senescence signaling and mitigates the intestinal fibrosis in IBDs

Inflammatory bowel disease (IBD), represents a wide range of intestinal disorders that commonly lead to an anomalous production and deposition of extracellular matrix (ECM) proteins and consequently to fibrosis. Despite much progress made in the last twenty years in the treatment of IBD, once the fibrogenesis process is onset, the only resolutive treatment for IBD complications is still the surgical approach. The main driver of fibrosis and epithelial-mesenchymal transition (EMT) is the transforming growth factor beta (TGF-β), as shown by the anti-fibrotic action exerted by several molecules able to modulate its signaling such as peroxisome proliferator-activated receptor (PPAR)-γ and its agonists. We investigated the contribution of AGE/R AGE (advanced glycation end products/receptor of AGEs), and the senescence pathways, other than the EMT in the context of the complex pathophysiology of IBD. We evaluated human biopsies from control and patients in remission stage of IBD, and a mouse model of colitis dextran sodium sulphate (DSS)-induced, treated or not with GED (PPAR-gamma-agonist), or 5-aminosalicylic acid (5-ASA), a reference drug commonly used in the IBD treatment. In the human samples, we highlighted an increase in EMT markers (β-catenin, E-cadherin, vimentin), AGE/RAGE signaling, and senescence (β-gal, MMP1, IL-1β) pathways, compared to controls. Coherently, we found overexpression of the same pathways in DSS-treated mice. Surprisingly, the GED can reduce all the pro-fibrotic signaling, often more efficiently than 5-ASA. Our data suggest that a molecule able to act simultaneously on multiple pathways involved in the fibrogenesis process could be a valid target candidate for IBD treatment. In this context, PPAR-γ activation, enhanced by an agonist such as GED, may represent a good strategy for mitigating IBD progression.