Metabolic modeling links gut microbiota to metabolic markers of Parkinson’s disease

Human gut microbiota have been implicated in metabolic disruptions in Parkinson's disease (PD). However, the underlying mechanisms linking gut microbiota to these disease-related metabolic changes remain largely unknown. In this study, we applied constraint-based metabolic modeling to identify potential causal links between compositional shifts in gut microbiota in PD and metabolic blood markers of PD. We personalized <i>in silico</i> whole-body metabolic models with gut metagenomics of 435 PD patients and 219 healthy controls and profiled <i>in silico</i> gut microbiome influences on 116 blood metabolites with replicated associations with PD diagnosis. Our analysis identified a reduced capacity of the PD host-microbiome co-metabolism to produce L-leucine and leucylleucine in blood. These metabolic predictions were traced back to lower L-leucine production of <i>Roseburia intestinalis</i> and higher L-leucine consumption by <i>Methanobrevibacter smithii</i> in PD microbiomes. We further predicted reduced host-microbiome production capacities of butyrate, myristic acid, and pantothenate in the blood of PD patients and linked these associations to reduced relative abundances of <i>Faecalibacterium prausnitzii</i>. Finally, lower nicotinic acid production capacities were predicted in PD patients, which were associated with increased relative abundances and increased nicotinic acid consumption of <i>Ruthenibacterium lactatiformans</i> in PD. In conclusion, we predicted that the gut microbiome can drive altered blood levels of six metabolites in PD and identified candidate microbial species that may influence these metabolic alterations. These findings may facilitate the development of novel therapies targeting the gut-brain axis in PD.