AI-guided use of balanced peroxisome proliferator-activated receptor a/g dual agonist finetunes macrophage responses in inflammatory bowel disease

Abstract

Abstract A computational platform, the Boolean network explorer (BoNE) has recently been developed; it enables querying and navigating invariant Boolean Implication Networks of disease maps for prioritizing high-value targets. Here we used BoNE derived Inflammatory Bowel Disease (IBD)-map and prioritize two nuclear receptors, PPARa and PPARg. Balanced agonism of PPARa/g was predicted to impact macrophage function, ameliorate colitis in network-prioritized animal models, ‘reset’ the gene expression network from disease to health. Predictions were validated using a balanced and potent PPARa/g-dual agonist (PAR5359) in two murine models, i.e., Citrobacter rodentium- and DSS-induced colitis. Mechanistically, we show that balanced dual agonists promote bacterial clearance more efficiently than individual agonists both in vivo and in vitro, through the controlled induction of pro-inflammatory cytokines, cellular ROS and gut-barrier protection. PPARa is required and its agonism is sufficient to induce the pro-inflammatory response that is essential for bacterial clearance and immunity, but PPARg-agonism blunts these responses, delays microbial clearance. Balanced agonists achieved controlled inflammation, barrier protection and reversed the network towards the healthy side of disease. When tested on IBD-patients-derived PBMCs, PAR5359 reversed the defective bacterial clearance observed in these subjects. These findings not only deliver a macrophage modulator in IBD but also highlight the potential of BoNE to accelerate and enhance the precision of drug discovery in various diseases.