Association of Fecal and Plasma Levels of Short-Chain Fatty Acids With Gut Microbiota and Clinical Severity in Parkinson Disease Patients

Background and Objectives: Short-chain fatty acids (SCFAs) are gut microbial metabolites that promote the disease process in a rodent model of Parkinson’s disease (PD), but fecal levels of SCFAs in PD patients are reduced. Simultaneous assessments of fecal and plasma SCFA levels, and their inter-relationships with the PD disease process are scarce. We aimed to compare fecal and plasma levels of different SCFAs subtypes in PD patients and healthy controls to delineate their interrelations and link to gut microbiota changes and clinical severity of PD. Methods: A cohort of 96 PD patients and 85 controls were recruited from National Taiwan University Hospital. Fecal and plasma concentrations of SCFAs were measured using chromatography and mass spectrometry. Gut microbiota was analyzed using metagenomic shotgun sequencing. Body mass index and medical co-morbidities were evaluated, and dietary information was obtained using a food frequency questionnaire. To assess motor and cognitive impairment, we used the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and the Mini-Mental Status Examination (MMSE). Results: Compared with controls, PD patients had lower fecal but higher plasma concentrations of acetate, propionate, and butyrate. After adjustment for age, sex, disease duration, and anti-PD medication dosage, MDS-UPDRS part III motor scores correlated with reduced fecal levels of acetate (ρ = -0.37, p = 0.012), propionate (ρ = -0.32, p = 0.036), and butyrate (ρ = -0.40, p = 0.004) and with increased plasma propionate concentrations (ρ = 0.26, p = 0.042) in PD patients. MMSE scores negatively correlated with plasma levels of butyrate (ρ = -0.09, p = 0.027) and valerate (ρ = -0.032, p = 0.033) after adjustment for confounders. SCFAs-producing gut bacteria correlated positively with fecal levels of SCFAs in healthy controls but revealed no association in patients with PD. In the PD patient group, the abundance of pro-inflammatory microbes, such as Clostridiales bacterium NK3B98 and Ruminococcus sp. AM07-15 , significantly correlated with decreased fecal levels and increased plasma levels of SCFAs, especially propionic acid. Discussion: Reductions in fecal SCFAs but increased plasma SCFAs were observed in PD patients and corelated to specific gut microbiota changes and the clinical severity of PD. Classification of evidence: This study provides Class III evidence that gut metabolite SCFAs distinguish between PD patients and controls, and are associated with disease severity in patients with PD.