By Virginia Gao, MD, PhD
Instructor in Neurology and Neuroscience, Weill Cornell Medical College
SYNOPSIS: A Mendelian randomization study shows that trimethylamine N-oxide (TMAO) and its precursor metabolites are not associated with risk of Parkinson’s disease (PD) but have both positive and negative causal effects on some indicators of PD severity and progression.
SOURCE: Zhou H, Luo Y, Zhang W, et al. Causal effect of gut-microbiota-derived metabolite trimethylamine N-oxide on Parkinson’s disease: A Mendelian randomization study. Eur J Neurol 2023;30:3451-3461.
Trimethylamine N-oxide (TMAO) is generated from the metabolism of betaine, carnitine, and choline by the gut microbiota. Increased serum levels have been linked to both worse motor and cognitive symptoms in Parkinson’s disease (PD), as well as decreased risk of PD progression and dementia. To determine the direction of a causal relationship, this study used a Mendelian randomization design, in which instrumental variable analysis is applied. The instrumental variable is related to the exposure, but not the outcome of interest, and the method assumes that genetic variants can serve as such an instrumental variable. The authors first determined single nucleotide polymorphisms (SNPs) associated with plasma levels of TMAO and its precursors using one data set, and then examined these SNPs in three PD data sets.
To determine SNPs associated with circulating levels of TMAO, betaine, carnitine, and choline, data were derived from a genome-wide association study (GWAS) where metabolite levels were measured in 2,076 participants in the Framingham Heart Study using liquid chromatography-mass spectrometry. These SNPs then were examined in other data sets to determine if they 1) play a role in risk of PD, with 33,674 cases and 449,056 controls examined; 2) play a role in progression of PD, using age of onset in 17,996 PD cases, and other indicators in 4,092 PD cases.
The other indicators included measures of more advanced, bilateral disease with impaired postural stability with or without the need for assistive mobility devices (Hoehn & Yahr stage 3 and above) and the presence of motor fluctuations including dyskinesia; the presence of non-motor symptoms (hyposmia, constipation, rapid eye movement sleep behavior disorder, depression, excessive daytime sleepiness, insomnia, and dementia); and clinical scales measuring cognition (Montreal Cognitive Assessment and Mini-Mental State Exam), and motor and other functional scales (Unified Parkinson’s Disease Rating Scale [UPDRS] and Schwab and England Activities of Daily Living Scale [SEADL]).
There was no causal effect of TMAO, betaine, carnitine, and choline on the risk of PD or the age of onset of PD. However, there was a possible causative effect of some of the other indicators of progression. Specifically, higher TMAO was related to reduced risk of motor fluctuation, and higher carnitine was related to reduced risk of insomnia. Conversely, higher betaine was related to higher risk of motor fluctuation, more advanced Hoehn & Yahr stage, and higher UPDRS motor score, while higher choline was related to higher UPDRS motor fluctuation score and higher SEADL score. The underlying mechanisms mediating these effects have yet to be determined.
COMMENTARY
The plasma level of TMAO is determined by diet, microbial flora, and hepatic flavin-containing monooxygenase activity. Plasma TMAO has been shown to increase with age, and there is a positive correlation between plasma levels of TMAO and increased risk of major cardiovascular events, thought to be related effects of TMAO on inflammation, changes in cholesterol metabolism, and thrombosis. TMAO also can be detected in the cerebrospinal fluid, although it is unknown whether it crosses the blood-brain barrier or could be synthesized directly in the brain. TMAO has been associated with various clinical aspects of Alzheimer’s disease and has been suggested to interact with a number of proteins thought to be involved in neurodegenerative pathophysiology, including amyloid beta, tau, and alpha-synuclein.
Immune and inflammatory mechanisms could tie together a role for TMAO in these various age-related diseases. Elevated TMAO is thought to have deleterious effects in a number of studies, but as the current study suggests, the relationship may be bidirectional or involve mechanisms yet to be identified.
The gut-brain axis contributes to disease pathophysiology through interactions between the central and enteric nervous system, microbiota-derived metabolites, and immunological mechanisms. Altogether, the role of gut dysbiosis in several brain disorders, including PD, now is well-established, although many aspects of the underlying pathophysiology remain to be determined and should be explored to further elucidate potential disease biomarkers and therapeutic targets.
