In Silico Integrated Systems Biology Analysis of Gut-Derived Metabolites from Philippine Medicinal Plants Against...

Atopic dermatitis (AD) is a multifactorial skin disorder characterized by immune and barrier dysfunction. The gut-skin axis is a bidirectional pathway through which gut and skin influence each other via microbial metabolites. Bioactive metabolites produced by microbial transformation of phytochemicals show potential for AD prevention. This study developed a computational systems biology pipeline that prioritized gut-derived metabolites from Philippine medicinal plants by integrating metabolite prediction, pharmacokinetics, network analysis, and molecular simulations. From 2231 predicted metabolites, 31 satisfied pharmacological criteria and were mapped to 199 AD-associated targets, with ALB, CASP3, and PPARG identified as hub genes. Two metabolites, THPOC and PM38, exhibited complementary target affinities and strong binding stability. THPOC stabilized ALB and CASP3, supporting barrier integrity and apoptosis regulation, while PM38 strongly engaged PPARG, modulating lipid metabolism and anti-inflammatory transcription. They exhibited comparable or superior docking scores, stable MD interactions, and favorable binding free energies, compared to abrocitinib, an approved AD treatment. DFT analysis confirmed electronic stability and donor-acceptor properties linked to target selectivity. These findings highlight THPOC and PM38 as promising immunometabolic modulators acting on key AD-related pathways. Collectively, this study introduces a reproducible systems-based computational discovery framework, offering a novel preventive strategy for AD.