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 Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 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 Clo tridiales 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. Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. INTRODUCTION Emerging evidence suggests that the pathological hallmarks of PD, Lewy bodies, originate in the gut enteric nervous system before the onset of motor dysfunction in patients with PD. Studies in rodent PD models have shown that α-synuclein aggregations could propagate from the enteric nervous system to the brainstem through the vagus nerve. 1, 2 Gastrointestinal symptoms may precede motor symptoms by decades. 3 This gut–brain hypothesis has led to numerous studies showing that PD patients have a distinct gut microbiota structure compared with controls and that changes in gut microbiota correlate with disease severity and progression. 4-6 Short-chain fatty acids (SCFAs) are the main metabolites produced by gut bacterial fermentation of dietary fiber and are speculated to be pivotal in gut–brain cross talks. 7, 8 SCFAs are absorbed in the colonocytes and transported to the liver via the portal venous system, and some SCFAs enter the systemic circulation. Acetic acid (C2), propionic acid (C3) and butyric acid (C4) are the most abundant SCFAs in the colon. 9 SCFAs have local effects in maintaining intestinal barrier integrity and shaping gut mucosal innate immunity. 10 They also have remote effects in the blood–brain barrier (BBB) by promoting tight junction proteins and crossing BBB to activate neurons through stimulation of G protein-coupled receptors. 11,12 An in vivo study using a transgenic α-synuclein–expressing mouse model demonstrated that a germ-free environment eliminates disease phenotypes but that oral feeding with SCFAs resurfaced PD-related neuropathology by augmenting neuroinflammation. 7 These findings suggest that SCFAs are required for the development of PD process. However, results for Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. SCFAs in PD patients conflict with these findings. Compared with healthy controls, PD patients have reduced fecal SCFAs and their producing bacteria compared to healthy controls. 8, 13, 14, 15 Only a few studies have reported on circulating levels of SCFAs in patients with PD. 17 An integrated study examining both fecal and plasma levels of SCFAs is still lacking. Hence, we aim to analyze and compare fecal and plasma levels of SCFAs in PD patients and unaffected controls to delineate the interrelations of these levels and link to changes in gut microbiota and clinical severity of PD. Primary research questions: Our primary research question was to determine whether fecal and plasma levels of SCFAs could distinguish patients with PD from controls and correlate with disease severity in patients with PD.