Exploring the therapeutic potential of the gut microbiota metabolite 3‑indolepropionic acid in parkinson's disease: a network pharmacology, molecular docking and cell viability study

Background the global burden of Parkinson's disease (PD) is rising, yet its pathogenesis remains incompletely understood. Growing evidence implicates the microbiota-gut-brain axis, especially metabolites gut microbiota, as key modulators of PD pathogenesis, but their precise molecular actions remain unclear. Methods using Global Burden of Disease data (1990-2021), we first characterized global epidemiological trends of PD. We identified gut microbiota metabolites and their key targets involved in PD by integrating network pharmacology and molecular docking. Functional enrichment highlighted Akt1 related signaling as a central hub. Finally, Cell Counting Kit 8 (CCK8) assays assessed the neuroprotective effects of selected compounds in 1-methyl-4-phenylpyridinium induced HT-22 neuronal cells. Results global PD prevalence increased from 3,148,395 (1990) to 11,767,272 (2021). Integration of 1,518 gut microbiota metabolite targets with 8,679 PD genes yielded 63 shared targets, among which Akt1, IL6, JUN, TP53, and NFKB1 emerged as hubs. Enrichment analyses highlighted pathways related to inflammation, cellular stress, and Apoptosis. Docking suggested favorable IPA-AKT1 binding (-7.553 kcal/mol), and IPA rescued viability in MPP⁺ treated HT‑22 cells (n = 6 per group, mean ± SD; P < 0.05 vs. MPP⁺ control), with significant gains versus MPP⁺ controls (P < 0.05). Conclusion this study integrates epidemiological analysis with computational and experimental approaches to reveal that gut microbiota metabolites, particularly IPA, may influence PD through Akt1 mediated regulation of neuroinflammatory and apoptotic pathways. The insight highlight gut microbiota metabolites as promising candidates for biomarker discovery and therapeutic exploration in PD.

3‑Indolepropionic Acid; AKT1; Gut microbiota; Neuroinflammation; Parkinson's disease.