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Background: Cerebral white matter hyperintensity (WMH) is a pivotal imaging feature of cerebral small vessel disease (CSVD), closely correlated with an elevated risk of ischemic stroke (IS). Trimethylamine N-oxide (TMAO), a metabolite of gut microbiota, is increasingly associated with IS and atherosclerosis. However, the intricate relationship between TMAO and WMH remains ambiguous. This study aimed to study the connection between plasma TMAO and WMH. Furthermore, it assessed the potential of TMAO as a risk evaluation instrument for WMH. Methods: In this cross-sectional study, we categorized WMH into periventricular WMH (P-WMH) and deep WMH (D-WMH), based on its locations. The severity of WMH was assessed and grouped according to the Fazekas scale. Plasma TMAO levels were quantitatively determined. We established the correlation between plasma TMAO levels and WMH severity using a Logistic regression model. Additionally, we employed ROC curves to evaluate the diagnostic efficacy of plasma TMAO concentration in distinguishing the severity of WMH. Results: A higher plasma TMAO tertile was significantly linked to a higher Fazekas score, encompassing the overall score, P-WMH score, and D-WMH score (p < 0.001). A logical regression analysis revealed that plasma TMAO levels were independently associated with overall moderate and severe WMH, compared to overall non-mild WMH, in the unadjusted model (OR = 1.373, 95%CI 1.183–1.594 for moderate; OR = 1.384, 95%CI 1.192–1.607 for severe), the adjusted model a (OR = 1.436, 95%CI 1.214–1.669 for moderate; OR = 1.446, 95%CI 1.222–1.711 for severe) and the adjusted model b (OR = 1.490, 95%CI 1.234–1.800 for moderate; OR = 1.494, 95%CI 1.237–1.805 for severe). The analysis also showed an independent correlation between plasma TMAO levels and WMH severity, irrespective of the unadjusted model, adjusted model a, or adjusted model b, when considering P-WMH and D-WMH severity. The ROC indicated that, in overall WMH and P-WMH, the area under curve (AUC) for non-mild and severe WMH were both>0.5, while the AUC for moderate WMH was<0.5. In contrast, in D-WMH, the AUC for non-mild, moderate, and severe WMH were all>0.5. Conclusion: Plasma TMAO levels exhibited a significant correlation with both overall and region-specific WMH severity. Furthermore, the plasma TMAO levels displayed robust predictive capability for D-WMH. [ABSTRACT FROM AUTHOR]

Objectives: The role of trimethylamine oxide (TMAO) in patients with cognitive impairment remains controversial. This study aimed to assess the association between TMAO and its precursors and the prevalence of cognitive impairment. Methods: PubMed, Embase, and Web of Science databases were searched for studies that met the inclusion criteria from their inception to 14 September 2024, and references were manually searched to identify any additions. Odds ratio (OR) was assessed by random-effects modeling, subgroup analyses to identify potential sources of heterogeneity, and the Newcastle-Ottawa Scale (NOS) and the Agency for Healthcare Research and Quality (AHRQ) Inventory for qualitative evaluation. Results: Nine studies involving 82,246 participants were included in the analysis. Meta-analyses suggested that elevated TMAO levels were strongly associated with an increased risk of cognitive impairment (OR: 1.39, 95% confidence interval [95%CI]: 1.09–1.77, p < 0.05, I2:60%), and consistent results were obtained across all subgroups examined and sensitivity analyses. However, in the TMAO dose–response meta-analysis and TMAO precursor meta-analyses, the results were not significantly different (dietary choline: OR: 0.93, 95%CI: 0.78–1.10, p = 0.385, I2:68%, plasma choline: OR: 0.65, 95%CI: 0.41–1.02, p = 0.063, I2:76%, plasma betaine: OR: 0.74, 95%CI: 0.52–1.05, p = 0.094, I2:61%). Conclusion: We found that high TMAO concentrations were positively associated with the risk of cognitive impairment. TMAO is expected to be a potential risk predictor and therapeutic target for cognitive impairment. However, more high-quality studies are needed to further investigate the dose relationship between circulating TMAO concentrations and cognitive impairment. Systematic review registration: PROSPERO, identifier: CRD42023464543. [ABSTRACT FROM AUTHOR]

Objectives: The role of trimethylamine oxide (TMAO) in patients with cognitive impairment remains controversial. This study aimed to assess the association between TMAO and its precursors and the prevalence of cognitive impairment. Methods: PubMed, Embase, and Web of Science databases were searched for studies that met the inclusion criteria from their inception to 14 September 2024, and references were manually searched to identify any additions. Odds ratio (OR) was assessed by random-effects modeling, subgroup analyses to identify potential sources of heterogeneity, and the Newcastle-Ottawa Scale (NOS) and the Agency for Healthcare Research and Quality (AHRQ) Inventory for qualitative evaluation. Results: Nine studies involving 82,246 participants were included in the analysis. Meta-analyses suggested that elevated TMAO levels were strongly associated with an increased risk of cognitive impairment (OR: 1.39, 95% confidence interval [95%CI]: 1.09-1.77, p < 0.05, I2:60%), and consistent results were obtained across all subgroups examined and sensitivity analyses. However, in the TMAO dose-response meta-analysis and TMAO precursor meta-analyses, the results were not significantly different (dietary choline: OR: 0.93, 95%CI: 0.78-1.10, p = 0.385, I2:68%, plasma choline: OR: 0.65, 95%CI: 0.41-1.02, p = 0.063, I2:76%, plasma betaine: OR: 0.74, 95%CI: 0.52-1.05, p = 0.094, I2:61%). Conclusion: We found that high TMAO concentrations were positively associated with the risk of cognitive impairment. TMAO is expected to be a potential risk predictor and therapeutic target for cognitive impairment. However, more highquality studies are needed to further investigate the dose relationship between circulating TMAO concentrations and cognitive impairment. [ABSTRACT FROM AUTHOR]

BackgroundCerebral white matter hyperintensity (WMH) is a pivotal imaging feature of cerebral small vessel disease (CSVD), closely correlated with an elevated risk of ischemic stroke (IS). Trimethylamine N-oxide (TMAO), a metabolite of gut microbiota, is increasingly associated with IS and atherosclerosis. However, the intricate relationship between TMAO and WMH remains ambiguous. This study aimed to study the connection between plasma TMAO and WMH. Furthermore, it assessed the potential of TMAO as a risk evaluation instrument for WMH.MethodsIn this cross-sectional study, we categorized WMH into periventricular WMH (P-WMH) and deep WMH (D-WMH), based on its locations. The severity of WMH was assessed and grouped according to the Fazekas scale. Plasma TMAO levels were quantitatively determined. We established the correlation between plasma TMAO levels and WMH severity using a Logistic regression model. Additionally, we employed ROC curves to evaluate the diagnostic efficacy of plasma TMAO concentration in distinguishing the severity of WMH.ResultsA higher plasma TMAO tertile was significantly linked to a higher Fazekas score, encompassing the overall score, P-WMH score, and D-WMH score (p 0.5, while the AUC for moderate WMH was0.5.ConclusionPlasma TMAO levels exhibited a significant correlation with both overall and region-specific WMH severity. Furthermore, the plasma TMAO levels displayed robust predictive capability for D-WMH.

Brain organoids are valuable research models for human development and disease since they mimic the various cell compositions and structures of the human brain; however, they have challenges in presenting aging phenotypes for degenerative diseases. This study analyzed the association between aging and the gut metabolite trimethylamine N-oxide (TMAO), which is highly found in the midbrain of elderly and Parkinson’s disease (PD) patients. TMAO treatment in midbrain organoid induced aging-associated molecular changes, including increased senescence marker expression (P21, P16), p53 accumulation, and epigenetic alterations. In addition, TMAO-treated midbrain organoids have shown parts of neurodegeneration phenotypes, including impaired brain-derived neurotrophic factor (BDNF) signaling, loss of dopaminergic neurons, astrocyte activation, and neuromelanin accumulation. Moreover, we found TMAO treatment-induced pathophysiological phosphorylation of α-synuclein protein at Ser-129 residues and Tau protein at Ser202/Thr205. These results suggest a role of TMAO in the aging and pathogenesis of the midbrain and provide insight into how intestinal dysfunction increases the risk of PD. Furthermore, this system can be utilized as a novel aging model for induced pluripotent stem cell (iPSC)-based modeling of late-onset diseases. [ABSTRACT FROM AUTHOR]

Background and purpose: The gut-brain axis is bidirectional and the imbalance of the gut microbiota usually coexists with brain diseases, including Alzheimer’s disease (AD). Accumulating evidence indicates that endoplasmic reticulum (ER) stress is a core lesion in AD and persistent ER stress promotes AD pathology and impairs cognition. However, whether the imbalance of the gut microbiota is involved in triggering the ER stress in the brain remains unknown. Materials and methods: In the present study, fecal microbiota transplantation (FMT) was performed with gut microbiota from AD patients and APP/PS1 mice, respectively, resulting in two mouse models with dysregulated gut microbiota. The ER stress marker protein levels in the cerebral cortex were assessed using western blotting. The composition of the gut microbiota was assessed using 16S rRNA sequencing. Results: Excessive ER stress was induced in the cerebral cortex of mice after FMT. Elevated ER stress marker proteins (p-perk/perk, p-eIF2a/eIF2a) were observed, which were rescued by 3,3-dimethyl-1-butanol (DMB). Notably, DMB is a compound that significantly attenuates serum trimethylamine- N-oxide (TMAO), a metabolite of the gut microbiota widely reported to affect cognition. Conclusion: The findings indicate that imbalance of the gut microbiota induces ER stress in the cerebral cortex, which may be mediated by TMAO. [ABSTRACT FROM AUTHOR]

Brain organoids are valuable research models for human development and disease since they mimic the various cell compositions and structures of the human brain; however, they have challenges in presenting aging phenotypes for degenerative diseases. This study analyzed the association between aging and the gut metabolite trimethylamine N -oxide (TMAO), which is highly found in the midbrain of elderly and Parkinson's disease (PD) patients. TMAO treatment in midbrain organoid induced aging-associated molecular changes, including increased senescence marker expression ( P21, P16 ), p53 accumulation, and epigenetic alterations. In addition, TMAO-treated midbrain organoids have shown parts of neurodegeneration phenotypes, including impaired brain-derived neurotrophic factor (BDNF) signaling, loss of dopaminergic neurons, astrocyte activation, and neuromelanin accumulation. Moreover, we found TMAO treatment-induced pathophysiological phosphorylation of α-synuclein protein at Ser-129 residues and Tau protein at Ser202/Thr205. These results suggest a role of TMAO in the aging and pathogenesis of the midbrain and provide insight into how intestinal dysfunction increases the risk of PD. Furthermore, this system can be utilized as a novel aging model for induced pluripotent stem cell (iPSC)-based modeling of late-onset diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lee, Kang, Ham, Son and Lee.)

Background and Purpose: The gut-brain axis is bidirectional and the imbalance of the gut microbiota usually coexists with brain diseases, including Alzheimer's disease (AD). Accumulating evidence indicates that endoplasmic reticulum (ER) stress is a core lesion in AD and persistent ER stress promotes AD pathology and impairs cognition. However, whether the imbalance of the gut microbiota is involved in triggering the ER stress in the brain remains unknown., Materials and Methods: In the present study, fecal microbiota transplantation (FMT) was performed with gut microbiota from AD patients and APP/PS1 mice, respectively, resulting in two mouse models with dysregulated gut microbiota. The ER stress marker protein levels in the cerebral cortex were assessed using western blotting. The composition of the gut microbiota was assessed using 16S rRNA sequencing., Results: Excessive ER stress was induced in the cerebral cortex of mice after FMT. Elevated ER stress marker proteins (p-perk/perk, p-eIF2α/eIF2α) were observed, which were rescued by 3,3-dimethyl-1-butanol (DMB). Notably, DMB is a compound that significantly attenuates serum trimethylamine-N-oxide (TMAO), a metabolite of the gut microbiota widely reported to affect cognition., Conclusion: The findings indicate that imbalance of the gut microbiota induces ER stress in the cerebral cortex, which may be mediated by TMAO., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Gu, Xu, Du, Zhao, Zhao and Liu.)