Gut microbiota-derived metabolite trimethylamine N-oxide as a biomarker in early Parkinson's disease

Chung, Seok Jong; Rim, John Hoon; Ji, Dajeong; Lee, Sang‐Won; Yoo, Hyung Sik; Jung, Jin Ho; Baik, Kyoung Won; Choi, Yonghoon; Ye, Byoung Seok; Sohn, Young H.; Yun, Mijin; Lee, Sang-Guk; Lee, Phil Hyu

doi:10.1016/j.nut.2020.111090

Cited by 40 publications

(37 citation statements)

References 61 publications

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“…Interpreting associations between circulating TMAO and cognition is further complicated by studies indicating that consumption of the TMAO precursors choline and l -carnitine can improve cognitive function [ 24 , 25 , 77 ], evidence that patients with Parkinson’s disease have lower circulating TMAO than healthy controls [ 78 ], and more-recent Mendelian randomisation analysis indicating that serum TMAO and Alzheimer’s disease are not causally related [ 79 ]. Given this background, our data indicating that physiologically relevant concentrations of TMAO have positive effects upon both BBB integrity and cognition in vivo thus serve as a useful counterweight to population-level correlation studies.…”

Section: Discussionmentioning

confidence: 99%

Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide

et al. 2021

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Background Communication between the gut microbiota and the brain is primarily mediated via soluble microbe-derived metabolites, but the details of this pathway remain poorly defined. Methylamines produced by microbial metabolism of dietary choline and l-carnitine have received attention due to their proposed association with vascular disease, but their effects upon the cerebrovascular circulation have hitherto not been studied. Results Here, we use an integrated in vitro/in vivo approach to show that physiologically relevant concentrations of the dietary methylamine trimethylamine N-oxide (TMAO) enhanced blood-brain barrier (BBB) integrity and protected it from inflammatory insult, acting through the tight junction regulator annexin A1. In contrast, the TMAO precursor trimethylamine (TMA) impaired BBB function and disrupted tight junction integrity. Moreover, we show that long-term exposure to TMAO protects murine cognitive function from inflammatory challenge, acting to limit astrocyte and microglial reactivity in a brain region-specific manner. Conclusion Our findings demonstrate the mechanisms through which microbiome-associated methylamines directly interact with the mammalian BBB, with consequences for cerebrovascular and cognitive function.

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Section: Discussionmentioning

confidence: 99%

Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide

et al. 2021

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Section: Discussionmentioning

confidence: 99%

“…Interpreting associations between circulating TMAO and cognition is further complicated by studies indicating that consumption of the TMAO precursors choline and L-carnitine can improve cognitive function 24,25,73 , evidence that patients with Parkinson's disease have lower circulating TMAO than healthy controls 74 , and more recent Mendelian randomisation analysis indicating that serum TMAO and Alzheimer's disease are not causally related 75 . Given this background, our data indicating that physiologically relevant concentrations of TMAO have positive effects upon both BBB integrity and cognition in vivo thus serve as a useful counterweight to population-level correlation studies.…”

Section: Tmao and Cognitive Functionmentioning

confidence: 99%

Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamineN-oxide

Hoyles

Pontifex

Rodríguez-Ramiro

et al. 2021

Preprint

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Communication between the gut microbiota and the brain is primarily mediated via soluble microbe-derived metabolites, but the details of this pathway remain poorly defined. Methylamines produced by microbial metabolism of dietary choline and L-carnitine have received attention due to their proposed association with vascular disease, but their effects upon the cerebrovascular circulation have not hitherto been studied. Here we use an integrated in vitro/in vivo approach to show that physiologically relevant concentrations of the dietary methylamine trimethylamine N- oxide (TMAO) enhanced and protected blood-brain barrier (BBB) integrity, acting through the tight junction regulator annexin A1. In contrast, the TMAO precursor trimethylamine (TMA) impaired BBB function and disrupted tight junction integrity. Moreover, we show that long-term exposure to TMAO has beneficial effects upon cognition in mice, improving visual recognition memory. Our findings demonstrate a direct interaction of microbiome-associated metabolites with the mammalian BBB, with consequences for cerebrovascular and cognitive function.

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“…Additionally, the GM was shown to regulate TMAO production via the impact on converting enzyme activity in the liver ( 117 ). However, in other neurodegenerative diseases lower plasma TMAO was reported to have worse prognostic implications ( 120 , 121 ). Altogether, the existing data indicate that the interaction between TMAO, its precursors and cognitive impairment is more complex than a direct link and GM may play in it one of the key roles.…”

Section: Microbiota-mediated Link Between Nutrition and Alzheimer's Diseasementioning

confidence: 99%

Nutrition, Gut Microbiota, and Alzheimer's Disease

Romanenko

Kholin

Koliada³

et al. 2021

Front. Psychiatry

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Nutrition is known to play an important role in the pathogenesis of Alzheimer's disease. Evidence is obtained that the gut microbiota is a key player in these processes. Dietary changes (both adverse and beneficial) may influence the microbiome composition, thereby affecting the gut-brain axis and the subsequent risk for Alzheimer's disease progression. In this review, the research findings that support the role of intestinal microbiota in connection between nutritional factors and the risk for Alzheimer's disease onset and progression are summarized. The mechanisms potentially involved in these processes as well as the potential of probiotics and prebiotics in therapeutic modulation of contributed pathways are discussed.

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Gut microbiota-derived metabolite trimethylamine N-oxide as a biomarker in early Parkinson's disease

Cited by 40 publications

References 61 publications

Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide

Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide

Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamineN-oxide

Nutrition, Gut Microbiota, and Alzheimer's Disease

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