Decreased levels of circulating trimethylamine N-oxide alleviate cognitive and pathological deterioration in transgenic mice: a potential therapeutic approach for Alzheimer’s disease

Gao, Qiang; Wang, Yuan; Wang, Xin; Fu, Shuang; Zhang, Xin; Wang, Ruitao

doi:10.18632/aging.102352

Cited by 74 publications

(59 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SCFAs demonstrate efficacy in interfering with protein-protein interactions that are indispensable for Aβ assemblies [ 76 ]. The microbial-derived metabolite trimethylamine N-oxide (TMAO) has been implicated in the pathogenesis of AD as well [ 77 ]. TMAO causes cognitive deterioration and pathological processes in AD by increasing β-secretase activity and thus aggravating Αβ accumulation [ 77 ].…”

Section: Roles Of the Microbiota-gut-brain Axis In The Pathogenesis Omentioning

confidence: 99%

Gut Microbiota and Dysbiosis in Alzheimer’s Disease: Implications for Pathogenesis and Treatment

et al. 2020

View full text Add to dashboard Cite

Understanding how gut flora influences gut-brain communications has been the subject of significant research over the past decade. The broadening of the term “microbiota-gut-brain axis” from “gut-brain axis” underscores a bidirectional communication system between the gut and the brain. The microbiota-gut-brain axis involves metabolic, endocrine, neural, and immune pathways which are crucial for the maintenance of brain homeostasis. Alterations in the composition of gut microbiota are associated with multiple neuropsychiatric disorders. Although a causal relationship between gut dysbiosis and neural dysfunction remains elusive, emerging evidence indicates that gut dysbiosis may promote amyloid-beta aggregation, neuroinflammation, oxidative stress, and insulin resistance in the pathogenesis of Alzheimer’s disease (AD). Illustration of the mechanisms underlying the regulation by gut microbiota may pave the way for developing novel therapeutic strategies for AD. In this narrative review, we provide an overview of gut microbiota and their dysregulation in the pathogenesis of AD. Novel insights into the modification of gut microbiota composition as a preventive or therapeutic approach for AD are highlighted.

show abstract

Section: Roles Of the Microbiota-gut-brain Axis In The Pathogenesis Omentioning

confidence: 99%

Gut Microbiota and Dysbiosis in Alzheimer’s Disease: Implications for Pathogenesis and Treatment

et al. 2020

View full text Add to dashboard Cite

show abstract

“…As Aβ plaques have been detected in the intestinal mucosa of both AD animal models and human patients, it is hypothesized that endogenous Aβ production starts in the gut and subsequently spreads to the CNS. Another possible mechanism that causes cognitive deterioration is a release of certain microbial-derived metabolites, such as trimethylamine N-oxide—a product of the metabolic transformation of dietary choline by the gut microbiota to trimethylamine, which is then oxidized by the host's liver ( Figure 2 ) ( 102 ). Both trimethylamine and its oxide are involved in aging and neurodegeneration.…”

Section: Microbiota In Different Nddsmentioning

confidence: 99%

Memorable Food: Fighting Age-Related Neurodegeneration by Precision Nutrition

et al. 2021

View full text Add to dashboard Cite

Healthcare systems worldwide are seriously challenged by a rising prevalence of neurodegenerative diseases (NDDs), which mostly, but not exclusively, affect the ever-growing population of the elderly. The most known neurodegenerative diseases are Alzheimer's (AD) and Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, but some viral infections of the brain and traumatic brain injury may also cause NDD. Typical for NDD are the malfunctioning of neurons and their irreversible loss, which often progress irreversibly to dementia and ultimately to death. Numerous factors are involved in the pathogenesis of NDD: genetic variability, epigenetic changes, extent of oxidative/nitrosative stress, mitochondrial dysfunction, and DNA damage. The complex interplay of all the above-mentioned factors may be a fingerprint of neurodegeneration, with different diseases being affected to different extents by particular factors. There is a voluminous body of evidence showing the benefits of regular exercise to brain health and cognitive functions. Moreover, the importance of a healthy diet, balanced in macro- and micro-nutrients, in preventing neurodegeneration and slowing down a progression to full-blown disease is evident. Individuals affected by NDD almost inevitably have low-grade inflammation and anomalies in lipid metabolism. Metabolic and lipid profiles in NDD can be improved by the Mediterranean diet. Many studies have associated the Mediterranean diet with a decreased risk of dementia and AD, but a cause-and-effect relationship has not been deduced. Studies with caloric restriction showed neuroprotective effects in animal models, but the results in humans are inconsistent. The pathologies of NDD are complex and there is a great inter-individual (epi)genetic variance within any population. Furthermore, the gut microbiome, being deeply involved in nutrient uptake and lipid metabolism, also represents a pillar of the gut microbiome–brain axis and is linked with the pathogenesis of NDD. Numerous studies on the role of different micronutrients (omega-3 fatty acids, bioactive polyphenols from fruit and medicinal plants) in the prevention, prediction, and treatment of NDD have been conducted, but we are still far away from a personalized diet plan for individual NDD patients. For this to be realized, large-scale cohorts that would include the precise monitoring of food intake, mapping of genetic variants, epigenetic data, microbiome studies, and metabolome, lipidome, and transcriptome data are needed.

show abstract

“…Numerous groups have investigated the putative relationship between TMAO and cognition following reports of an association between cerebrospinal fluid TMAO content and Alzheimer's disease 28 , with negative correlations between plasma TMAO content and cognitive function having been identified in both clinical [65][66][67] and experimental 29,68,69 settings. Whether this relationship is truly deterministic remains unclear, however, as the role of the immediate precursor to TMAO, TMA, in cognition and vascular function has largely been overlooked.…”

Section: Tmao and Cognitive Functionmentioning

confidence: 99%

“…Beyond vascular health, dietary methylamines have implications for cognition, with a positive correlation observed between choline intake and cognitive function in both humans 24,25 and mice 26,27 . In contrast, cerebrospinal fluid TMAO levels have been indicated as predictive of cognitive decline in Alzheimer's disease 28 , while suppression of microbial TMA/TMAO production improves cognitive function in the murine APP/PS1 model of Alzheimer's disease 29 . Given the disparities in the literature regarding the effects of methylamines upon the vasculature, and our increasing awareness of the BBB as a major actor in the pathology of multiple neurological conditions, we investigated the effects of physiologically relevant concentrations of TMAO and its precursor TMA upon BBB integrity and cognitive behaviour.…”

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

Decreased levels of circulating trimethylamine N-oxide alleviate cognitive and pathological deterioration in transgenic mice: a potential therapeutic approach for Alzheimer’s disease

Cited by 74 publications

References 62 publications

Gut Microbiota and Dysbiosis in Alzheimer’s Disease: Implications for Pathogenesis and Treatment

Gut Microbiota and Dysbiosis in Alzheimer’s Disease: Implications for Pathogenesis and Treatment

Memorable Food: Fighting Age-Related Neurodegeneration by Precision Nutrition

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

Contact Info

Product

Resources

About