Association of Trimethylamine N-Oxide and Its Precursor With Cerebral Small Vessel Imaging Markers

Chen, Yiyi; Xu, Jin; Pan, Yuesong; H, Yan; Jing, Jing; Yang, Yingying; Wang, Xing; Wan, Huijuan; Gao, Ying; Han, Shangrong; Zhong, Xi; Liu, Chenhui; Li, Zhengyang; Luo, Biyang; Wang, Guangyao; Zhao, Yilong; Wang, Nan; Lin, Jinxi; Meng, Xia; Zhao, Xingquan; Liu, Liping; Li, Wei; Jiang, Yong; Li, Zixiao; Zhang, Xinmiao; Yang, Xiaomeng; Ji, Ruijun; Wang, Chunjuan; Li, Hao; Wang, Penglian; Zheng, Huaguang; Ji, Weizhong; Cai, Xueli; Wu, Songdi; Han, Xuan; Wang, Yongjun

doi:10.3389/fneur.2021.648702

Cited by 12 publications

(9 citation statements)

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“…Accumulating evidence has proven the causal links among TMAO, CAD, and stroke (Witkowski et al, 2020). Elevated TMAO and choline levels have recently been found to be associated with severe WMHs, especially P-WMH (Chen et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Gut-Derived Metabolite Phenylacetylglutamine and White Matter Hyperintensities in Patients With Acute Ischemic Stroke

Feng

et al. 2021

Front. Aging Neurosci.

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Background: White matter hyperintensity (WMH) burden is associated with a higher risk of ischemic stroke. Phenylacetylglutamine (PAGln) is a gut microbiota-derived metabolite that may induce cardiovascular events by activating platelets and increasing the risk of thrombosis. The relationship between plasma PAGln and WMH burden in patients with ischemic stroke is unknown. This study was designed to investigate the association between plasma PAGln and WMH burden in patients with acute ischemic stroke.Methods: A total of 595 patients with acute ischemic stroke were enrolled in this study within 14 days of symptom onset. The burden of WMH was evaluated using the Fazekas scale based on the fluid-attenuated inversion recovery sequence. The severity of overall WMH was defined as none–mild WMH (total Fazekas score 0–2) or moderate–severe WMH (total Fazekas score 3–6). Based on the severity of periventricular WMH (P-WMH) and deep WMH (D-WMH), patients were categorized into either a none–mild (Fazekas score 0–1) group or a moderate–severe (Fazekas score 2–3) group. Plasma PAGln levels were quantified using liquid chromatography–mass spectrometry.Results: We found that patients with moderate–severe overall WMH showed higher plasma PAGln levels than patients with none–mild overall WMH, and similar results were found in the analyses according to P-WMH and D-WMH. The logistic regression analysis showed that the fourth PAGln quartile was independently associated with moderate–severe overall WMH (adjusted 95% CI 1.134–4.018) and P-WMH (adjusted 95% CI 1.174–4.226).Conclusion: These findings suggest that higher plasma PAGln levels are associated with moderate–severe overall WMH and P-WMH in patients with acute ischemic stroke.

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Section: Discussionmentioning

confidence: 99%

Gut-Derived Metabolite Phenylacetylglutamine and White Matter Hyperintensities in Patients With Acute Ischemic Stroke

Feng

et al. 2021

Front. Aging Neurosci.

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“… 21 Similarly, another recent study which detected the relationships of trimethylamine N-oxide with PV-WMH and D-WMH in a large cohort of TIA/AIS patients found that elevated trimethylamine N-oxide levels were associated with a higher risk of WMH burden, and more closely associated with PV-WMH than D-WMH. 40 We speculate that the discrepancy may be attributed to anatomical, histological as well as pathophysiological differences between PV-WMH and D-WMH. Previous histopathological studies have demonstrated that PV-WMH contained more immunoreactive microglia and astrocytes than D-WMH.…”

Section: Discussionmentioning

confidence: 82%

Serum YKL-40 Levels and White Matter Hyperintensities in Patients with Acute Ischemic Stroke

Shi¹,

Ke²,

Gong³

et al. 2023

JIR

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Background White matter hyperintensity (WMH) is associated with risk of acute ischemic stroke (AIS) and poor outcomes after AIS. The purpose of this prospective study was to evaluate the association between serum YKL-40 levels and WMH burden in patients with AIS. Methods From February 2020 to March 2021, a total of 672 consecutive AIS patients with magnetic resonance imaging data were prospectively recruited form two centers. Serum YKL-40 levels were quantified using enzyme-linked immunosorbent assay. The burden of WMH was semiquantitatively measured by the Fazekas visual grading scale. According to severity of overall WMH, patients were dichotomized into none–mild WMH group (Fazekas score 0–2) or moderate–severe WMH group (Fazekas score 3–6). Besides, based on severity of periventricular WMH (PV-WMH) and deep WMH (D-WMH), patients were categorized as none–mild (Fazekas score 0–1) or moderate–severe (Fazekas score 2–3). Results Among the 672 patients, 335 (49.9%) participants were identified with moderate–severe overall WMH, 326 (48.5%) with moderate–severe PV-WMH and 262 (39.0%) with moderate–severe D-WMH. Compared with the first quartile of serum YKL-40, the adjusted odds ratio (OR) of the fourth quartile for moderate–severe PV-WMH was 2.473 (95% confidence interval [CI] 1.316–4.646; P =0.005). No significant association was observed between YKL-40 and overall WMH (OR 0.762; 95% CI 0.434–1.336; P =0.343) or D-WMH (OR 0.695; 95% CI 0.413–1.171; P =0.172). Conclusion Our results suggested that higher YKL-40 levels appeared to be associated with PV-WMH, but not with overall WMH or D-WMH in patients with AIS.

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“…We found that the WMH signal of SHR rats was significantly severe compared with age-matched WKY rats, and 35-week SHR rats developed stronger WMH signals than 24-week SHR rats, indicating that the development of hypertension promoted the severity of WML with age ( Figure 1B ). TMAO, a gut microbiota metabolite, is reported to be correlated with WMH in CSVD and the development of hypertension ( Liu et al, 2019 ; Chen et al, 2021 ). Hereon, we detected the change of TMAO concentration in SHR and WKY rats.…”

Section: Resultsmentioning

confidence: 99%

“…And we also found a slight increase of TMAO level in 35-week SHR in comparison with 24-week SHR and TMAO was positively involved in the decreased volumes of white matter, indicating that TMAO might be correlated with the development of WML. The increased TMAO level is strongly associated with the severity of WMH ( Chen et al, 2021 ). Govindarajulu et al (2020) reported that TMAO could enhance endoplasmic reticulum stress to induce impairment in synaptic plasticity, contributing to cognitive deficits in Alzheimer’s model and insulin resistance mouse.…”

Section: Discussionmentioning

confidence: 99%

“…And obstructive sleep apnea combined with a high salt diet results in an increase in blood TMAO levels and a reduction of anti-inflammatory factors, contributing to the aggravation of hypertension in rats ( Liu et al, 2019 ), showing that the increased TMAO levels may be associated with the development of hypertension to some extent. Besides, the high TMAO level is positively correlated with the severity of WMH signal in cerebral small vessel imaging ( Chen et al, 2021 ). And accumulating studies have shown that TMAO can cross the blood-brain barrier (BBB) and exert a crucial role in cerebrospinal fluid (CSF) ( Vernetti et al, 2017 ; Vogt et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Trimethylamine N-oxide promotes demyelination in spontaneous hypertension rats through enhancing pyroptosis of oligodendrocytes

Tian

Niu

et al. 2022

Front. Aging Neurosci.

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BackgroundHypertension is a leading risk factor for cerebral small vessel disease (CSVD), a brain microvessels dysfunction accompanied by white matter lesions (WML). Trimethylamine N-oxide (TMAO), a metabolite of intestinal flora, is correlated with cardiovascular and aging diseases. Here, we explored the effect of TMAO on the demyelination of WML.MethodsSpontaneous hypertension rats (SHRs) and primary oligodendrocytes were used to explore the effect of TMAO on demyelination in vivo and in vitro. T2-weighted magnetic resonance imaging (MRI) was applied to characterize the white matter hyperintensities (WMH) in rats. TMAO level was evaluated using LC-MS/MS assay. The histopathological changes of corpus callosum were measured by hematoxylin-eosin and luxol fast blue staining. And the related markers were detected by IHC, IF and western blot assay. Mito Tracker Red probe, DCFH-DA assay, flow cytometry based on JC-1 staining and Annexin V-FITC/PI double staining were conducted to evaluate the mitochondrial function, intracellular ROS levels and cell apoptosis.ResultsSHRs exhibited stronger WMH signals and a higher TMAO level than age-matched normotensive Wistar-kyoto rats (WKY). The corpus callosum region of SHR showed decreased volumes and enhanced demyelination when treated with TMAO. Furthermore, TMAO significantly elevated ROS production and induced NLRP3 inflammasome and impairment of mitochondrial function of oligodendrocytes. More importantly, TMAO enhanced the pyroptosis-related inflammatory death of oligodendrocytes.ConclusionTMAO could cross the blood-brain barrier (BBB) and promote oligodendrocytes pyroptosis via ROS/NLRP3 inflammasome signaling and mitochondrial dysfunction to promote demyelination, revealing a new diagnostic marker for WML under hypertension.

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Association of Trimethylamine N-Oxide and Its Precursor With Cerebral Small Vessel Imaging Markers

Cited by 12 publications

References 50 publications

Gut-Derived Metabolite Phenylacetylglutamine and White Matter Hyperintensities in Patients With Acute Ischemic Stroke

Gut-Derived Metabolite Phenylacetylglutamine and White Matter Hyperintensities in Patients With Acute Ischemic Stroke

Serum YKL-40 Levels and White Matter Hyperintensities in Patients with Acute Ischemic Stroke

Trimethylamine N-oxide promotes demyelination in spontaneous hypertension rats through enhancing pyroptosis of oligodendrocytes

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