Fig. 8: Summary of findings and working model.
Schematic summarizes key approaches and findings of this study. First, network-rationalized target identification (Left) was performed using a web-based platform that queries > 1000 IBD datasets [ref. 9; see Methods] that served as ‘input’ to create a map of gene clusters that are progressively altered in the gut in the setting of IBD. Predictions are used to guide the choice of therapeutics (dual agonists of PPARα and PPARγ that have a balanced agonistic potential for both PPARs), the choice of animal models of IBD, predict cell types of action (macrophage processes), and finally, the subtype of IBD that could benefit most based on the cell type of action (i.e., CD). Second, experimentally determined mechanism of action studies (right, top) showed that balanced actions of both PPARα and PPPARγ enable the induction of bacterial clearance, resolution of inflammation, and healing; PPARα is responsible for ROS and cytokine induction, whereas PPPARγ is responsible for anti-inflammatory response and healing. The dual agonistic action was superior to each agonist used alone. Third, targets validation studies (right, bottom) in murine and human models confirm the use of PPARα/γ dual agonists for enhancing bacterial clearance and protection against colitis. When tested side-by-side in the infectious colitis model, the dual agonistic action was superior to each agonist used alone.
