Dataset Information

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

ABSTRACT: A computational platform, Boolean network explorer (BoNE), has recently been developed to infuse AI-enhanced precision into drug discovery; it enables 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, 'reset' the gene expression network from disease to health. Predictions were validated using a balanced and potent PPARα/γ-dual-agonist (PAR5359) in Citrobacter rodentium- and DSS-induced murine colitis models. Using inhibitors and agonists, we show that balanced-dual agonism promotes bacterial clearance efficiently than individual agonists, both in vivo and in vitro. PPARα is required and 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; 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.

SUBMITTER: Katkar GD

PROVIDER: S-EPMC8921270 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Katkar Gajanan D GD Sayed Ibrahim M IM Anandachar Mahitha Shree MS Castillo Vanessa V Vidales Eleadah E Toobian Daniel D Usmani Fatima F Sawires Joseph R JR Leriche Geoffray G Yang Jerry J Sandborn William J WJ Das Soumita S Sahoo Debashis D Ghosh Pradipta P

Communications biology 20220314 1

A computational platform, Boolean network explorer (BoNE), has recently been developed to infuse AI-enhanced precision into drug discovery; it enables 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 col ...[more]

PMID: 35288651

Similar Datasets

Project description:IntroductionInflammatory Bowel Disease (IBD), encompassing Crohn's disease and ulcerative colitis, presents significant clinical challenges due to its heterogeneous nature and complex etiology. Recent advancements in biomedical research have enhanced our understanding of IBD's genetic, microbial, and biochemical aspects. However, persistent issues in clinical management, including treatment non-response, surgical interventions, and diagnostic uncertainties, underscore the need for more targeted approaches. This review examines the convergence of artificial intelligence (AI) and precision medicine (PM) in IBD management. By leveraging AI's capacity to analyze complex, multi-dimensional datasets, this emerging field offers promising applications in improving diagnostic accuracy, predicting treatment responses, and forecasting disease progression, potentially transforming IBD patient care.MethodThe systematic review (SR) was conducted by searching the following databases: PubMed, PubMed PMC, BVS, Scopus, Web of Science, Embase, Cochrane, and ProQuest up to February 2024. Studies that employed AI in IBD applied to precision medicine were included.Results139 studies on applying AI in precision medicine for IBD were identified. Most studies (>70%) were published after 2020, indicating a recent surge in interest. The AI applications primarily focused on diagnosis, treatment response prediction, and prognosis. Machine learning algorithms were predominantly used, particularly random forest, logistic regression, and support vector machines. Omics data were frequently employed as predictors, especially transcriptomics and microbiome analyses. Studies demonstrated good predictive performance across all three areas, with median AUC values ranging from 0.85 to 0.90.ConclusionAI applications in IBD show promising potential to enhance clinical practice, particularly in disease prognosis and predicting treatment response. However, clinical implementation requires further validation through prospective studies. Future research should focus on standardizing protocols, defining clinically significant outcomes, and evaluating the efficacy of these tools.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets