Abstract:

Objective To investigate the clinical characteristics of non-motor symptoms (NMS) in patients with Parkinson's disease (PD) living at mid-to-high altitude, and to explore their associations with gut microbiota composition, plasma short-chain fatty acids (SCFAs), and inflammatory cytokine levels. Methods A cross-sectional study was conducted. Patients with PD who had long-term residence at mid-to-high altitude areas (Xining, altitude approximately 2295 m; Hainan Prefecture, altitude >3000 m) were enrolled as the PD group (n=45), and age-, sex-, and ethnicity-matched healthy individuals were enrolled as the healthy control group (HC group, n=45). NMS were assessed using the Non-Motor Symptoms Questionnaire (NMSQuest), the Parkinson's Disease Sleep Scale (PDSS), and the Hospital Anxiety and Depression Scale (HADS), while motor symptoms were evaluated using Part III of the Unified Parkinson's Disease Rating Scale (UPDRS-III). Morning stool samples and fasting venous blood samples were collected. Gut microbiota was analyzed by 16S rRNA gene sequencing. Plasma SCFAs, including acetate, propionate, and butyrate, were measured by gas chromatography-mass spectrometry. Plasma interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) levels were determined by enzyme-linked immunosorbent assay. Group differences were compared, and Spearman correlation analysis and multivariable linear regression were used to examine associations among variables. Results Compared with the HC group, the PD group had significantly higher total NMSQuest scores, HADS-A scores, and HADS-D scores (all P<0.01), PDSS scores significantly lower(P<0.01), as well as a higher prevalence of constipation (82.2% vs 31.1%, P<0.01). The PD group showed lower gut microbiota α-diversity (Shannon index) than the HC group (P<0.05), and significant differences in β-diversity were observed (PERMANOVA, P=0.001). At the genus level, the abundance of Prevotella was significantly decreased in the PD group, whereas the abundance of unclassified Enterobacteriaceae and Lactobacillus was significantly increased (all P<0.05). Correlation analysis showed that in patients with PD, Prevotella abundance was positively correlated with plasma butyrate levels (r=0.462, P=0.002) and negatively correlated with HADS-D scores (r=-0.384, P=0.010). Plasma butyrate levels were negatively correlated with HADS-D scores (r=-0.356, P=0.018) and TNF-α levels (r=-0.332, P=0.028). Mediation analysis suggested that plasma butyrate partially mediated the association between Prevotella abundance and depressive symptoms (HADS-D score), accounting for 21.7% of the total effect. Conclusion Patients with PD living at mid-to-high altitude bear a substantial NMS burden, particularly with prominent sleep disturbance, anxiety, depression, and constipation. Their gut microbiota composition is dysregulated, characterized by a reduction in butyrate-producing bacteria and an increase in potentially pro-inflammatory bacteria. Such microbial imbalance may contribute to NMS, including depression, by reducing butyrate production and exacerbating systemic inflammation. This study provides new insights into NMS management in PD at high altitude and into interventions targeting the gut-brain axis.

Key words: Parkinson’s disease, high altitude, non-motor symptoms, gastrointestinal microbiome, short-chain fatty acids, neuroinflammation