Artificial intelligence-rationalized balanced PPARα/γ dual agonism resets dysregulated macrophage processes in inflammatory bowel disease
Year: 2022
Type: article
Abstract: 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 . PPARa 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 PPARg-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.
Source: Communications Biology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,490
Funders: American Association of Immunologists, Leona M. and Harry B. Helmsley Charitable Trust, National Institutes of Health, University of California, San Diego, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Biomedical Imaging and Bioengineering, National Center for Advancing Translational Sciences
Awards: G1476237564, Macrophage Polarization in Response to Infections and Inflammation, Illumina NovaSeq 6000 Sequencing System, G4221725467, Innate responses following infection with enteric microbes, Modulation of Macrophage Polarization by Heterotrimeric G proteins: Implications of Gastrointestinal Inflammation, G5347599341, G5490462501, Annotation of cell types in human colon tissue using Boolean analysis, Network-Based Novel Therapeutics in Colorectal Cancers, Precision therapeutics of inflammatory bowel disease guided by Boolean logic, San Diego Digestive Diseases Research Center, Training in Multi-scale Analysis of Biological Structure and Function
OpenAlex ID: W4221082622