Multi-scale diversity analysis reveals scale-dependent microbial alterations in Parkinson's disease

Intestinal dysbiosis is closely related to the progression of Parkinson's disease (PD), affecting gut barrier integrity, immune responses, and hormonal regulation. This microbial imbalance is believed to modulate PD pathogenesis via the brain–gut axis, suggesting that gut microbiome complexity could have a substantial impact on disease progression. To systematically characterize microbial diversity patterns in PD, we reanalyzed 2,102 gut microbiome samples from eight independent studies using a multi-scale diversity framework: Hill numbers for alpha diversity, the Anna Karenina Principle (AKP) for beta diversity, and diversity–area relationships for gamma diversity. Alpha diversity showed statistically significant differences between Parkinson's disease (PD) patients and healthy controls in 25–38% of comparisons, while the remaining 62–75% demonstrated no significant differences. This distribution aligns with the 1/3 diversity–disease relationship conjecture—a pattern initially observed across different diseases (Ma et al. 2019, The ISME Journal), but which our findings now extend to multiple independent studies of the same disease (PD). Beta diversity analysis showed increasing AKP adherence with diversity order: at q = 0 (species richness), 38% of datasets followed AKP, rising to 63% at q = 1 (common species) and q = 2 (dominant species), indicating stronger dysbiosis signals among dominant community members. Gamma diversity analysis showed PD patients harbored 863 total, 64 common, and 28 dominant species versus 894, 57, and 26 in controls, with only common species differing significantly. Overall, PD gut microbiomes exhibit scale-dependent diversity alterations, underscoring the value of integrated diversity frameworks for understanding Parkinson's pathogenesis. • Reanalyzed 2,102 gut microbiomes from eight Parkinson’s disease cohorts. • Used unified alpha–beta–gamma diversity framework (Hill, AKP, DAR). • Confirmed the “one-third” diversity–disease conjecture within PD datasets. • AKP adherence increased from rare to dominant species, revealing dysbiosis. • Gamma diversity differed mainly in common species, showing scale dependence. This multi-scale diversity analysis of 2,102 gut microbiome samples reveals that Parkinson's disease exhibits scale-dependent microbial alterations—with alpha diversity differences in only 25-38% of cases following the 1/3 diversity-disease rule, increasing Anna Karenina Principle adherence for dominant species, and significant gamma diversity variations specifically in common species—highlighting the importance of integrated diversity frameworks in understanding the pathogenesis of Parkinson's disease.