Bile acids (BA) are increasingly recognized as signaling molecules involved in metabolic regulation and inflammatory processes, both of which are relevant to Parkinson’s disease (PD). However, their role in PD and disease progression remains unclear. In this study, plasma BA profiles were analyzed in 113 participants, including early- and advanced-stage PD patients and age- and sex-matched controls, across three time points over three years. Targeted metabolomics using LC-MS was applied to quantify 20 BA, complemented by analyses of functional ratios, including unconjugated/conjugated and hydrophobic/hydrophilic BA ratios and correlation patterns between BA species. Although most individual BA did not show consistent longitudinal changes, pooled analysis identified significant differences in the unconjugated/conjugated BA ratio between PD patients and controls. In contrast, the hydrophobic/hydrophilic ratio did not differ significantly between groups. Correlation analysis revealed differences in selected BA interrelationships, particularly involving primary and secondary BA, while the overall network structure remained largely preserved. These results indicate that BA metabolism in PD might be characterized rather by subtle, distributed alterations than pronounced changes in individual metabolites. BA profiling may therefore contribute to a broader metabolic characterization of PD, but its utility as a standalone biomarker appears limited.

Parkinson’s disease (PD) is associated with systemic proteostatic failure, chronic neuroinflammation, and mitochondrial abnormalities linked to severe oxidative stress. This exploratory longitudinal study mapped the deep-coverage plasma proteome (~6000 proteins via SOMAmer technology) in 32 patients with mild-to-moderate PD following a 21-day intensive, multimodal physiological stimulus framework. This hormetic intervention combined balneo- and hydropinic therapy (incorporating mineral water with 7.48 mg/L H₂S and peloid mud with 6.14% S²⁻ of dry matter), neurophysiotherapy, a neuroprotective MIND diet, mindfulness meditation, and clinical aromatherapy. Systems-level pathway analysis was leveraged to evaluate alterations in functional biological networks. Gene Set Enrichment Analysis (GSEA) resolved a negative enrichment of the Parkinson’s disease pathway hsa05012 (FDR = 0.0053). Network topology modeling revealed a highly coordinated proteostatic and antioxidant alteration pattern involving interferon-gamma (IFN-γ) and polyubiquitin-B (UBB) protein clusters (p = 2.2 × 10⁻⁵), accompanied by the downregulation of protein clearance markers (UBB, p62, and UCHL1). Concurrently, upregulation of the phase-II detoxification modifier sulfotransferase 1C2 (SULT1C2; log₂FC = 0.42) and a reduction of circulating mitochondrial respiratory subunits (NDUFB6, COX5A, NDUFB11) were observed. These exploratory findings may suggest that multimodal hormetic interventions trigger systemic, redox-responsive changes in protein signatures. However, because the distinct volatile chemical and organoleptic properties of the intervention prevent a sham control, these open-label findings must be treated as hypothesis-generating. These tentative models require verification in future parallel-controlled trials before definitive causal interpretations can be established.