Artificial Intelligence-rationalized balanced PPARα/γ dual agonism resets the dysregulated macrophage processes in inflammatory bowel disease

Abstract

A computational platform, the Boolean network explorer (BoNE), has recently been developed to infuse AI-enhanced precision into drug discovery; it enables querying and navigating invariant Boolean Implication Networks of disease maps for prioritizing high-value targets. Here we used BoNE to query an Inflammatory Bowel Disease (IBD)-map and prioritize a therapeutic strategy that involves dual agonism of two nuclear receptors, PPARα/γ. Balanced agonism of PPARα/γ was predicted to modulate macrophage processes, ameliorate colitis in network-prioritized animal models, reset the gene expression network from disease to health, and achieve a favorable therapeutic index that tracked other FDA-approved targets. Predictions were validated using a balanced and potent PPARα/γ-dual agonist (PAR5359) in two pre-clinical murine models, i.e., Citrobacter rodentium-induced infectious colitis and DSS-induced colitis. Using a combination of selective inhibitors and agonists, we show that balanced dual agonism promotes bacterial clearance more efficiently than individual agonists, both in vivo and in vitro. PPARα is required and its agonism is sufficient to induce the pro-inflammatory cytokines and cellular ROS, which are essential for bacterial clearance and immunity, whereas PPARγ-agonism blunts these responses, delays microbial clearance and induces the anti-inflammatory cytokine, IL10; balanced dual agonism achieved controlled inflammation while protecting the gut barrier and reversal of the transcriptomic network. Furthermore, dual agonism reversed the defective bacterial clearance observed in PBMCs derived from IBD patients. These findings not only deliver a macrophage modulator for use as barrier-protective therapy in IBD, but also highlight the potential of BoNE to rationalize combination therapy.

Coupling of NOD2 to GIV is Required for Bacterial Sensing

“…We asked if the protective actions of MDP require GIV. Compared to WT controls, the GIV-KO mice developed significantly worse DSS-induced acute colitis ( Fig 3A ), as determined by histological composite scores accounting for deformation of colon crypts and increased immune infiltration in the colon ( Fig 3B-C ) and disease activity index ( Fig 3D-E ); the latter is a composite score of stool consistency, weight loss and the presence of fecal blood (Katkar et al 2021; Swanson et al 2020; Whittem et al 2010) . Pre-treatment with MDP ameliorated the severity of colitis in WT, but not GIV-KO mice ( Fig 3B-E ).…”

A Living Organoid Biobank of Crohn’s Disease Patients Reveals Molecular Subtypes for Personalized Therapeutics

“…For example, the pan-JAK-inhibitor Tofacitinib has succeeded in Phase III trials for UC, with conflicting results in CD 76 , and our findings suggest that targeted trials on the S2FCD molecular subtype using JAK1/2-selective inhibitors (e.g., Upadacitinib, Filgotinib or Baricitinib) may have demonstrable efficacy. As for IDICD, the strategy of improving microbial clearance using the balanced dual-PPARα/γ agonism with PAR5359 was identified using an AI-guided network transcriptomics approach 20,72 , which is predicted to protect the gut mucosal barrier in IBD and represents a new class of therapy in IBD yet to enter clinical trials.…”

“…These findings agree with the prior findings of downregulated transcripts of multiple cytokines (Figure 2D-bottom left) and confirm the presence of an immune suppressed state in the setting of infection. We asked if impaired bacterial clearance in CD-EDMs can be reversed by a balanced dual agonist of PPARα/γ, PAR5359 71 , which has recently been shown to accelerate bacterial clearance in CD-patient derived PBMCs and ameliorate colitis in both DSS-induced chemical and Citrobacter-induced infectious colitis models 72 . We found that treatment of the CD-EDMs with PAR5359 significantly reduced the bacterial burden (Figure 5I-right), with virtually no effect on healthy-EDMs (Figure 5I-left).…”

Parsing the Role of PPARs in Macrophage Processes

“…We have demonstrated the dueling relationship between PPARγ and PPARα in terms of macrophage differentiation, bacterial and viral clearance, IBD, and atherosclerosis. A PPARγ/α dual agonist seems to be more promising in terms of therapeutics and activation of both receptors would counter the each other’s side effects while still providing better pharmacological effects ( 184 ). Another notable example is how PPARγ agonists have been used as a therapeutic drug for increasing insulin resistance in diabetic patients as well as lipid metabolism in patients with atherosclerosis.…”