The Prognostic Biomarkers of Plasma Trimethylamine N-Oxide and Short-Chain Fatty Acids for Recanalization Therapy in Acute Ischemic Stroke

Chou, Ping-Song; Yang, I-Hsiao; Kuo, Chang-Hung; Wu, Meng‐Ni; Lin, Tzu-Chao; Fong, Yi-On; Juan, Chi‐Hung; Lai, Chiou-Lian

doi:10.3390/ijms241310796

Cited by 5 publications

(4 citation statements)

References 34 publications

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“…Notably, isovalerate was found to be associated with the BMB outcome. A previous study has revealed that elevated plasma levels of isovalerate, a branched short-chain fatty acid, were observed following acute AIS reperfusion therapy, correlating with the severity and disability of stroke [63]. In another casecontrol study, elevated levels of linoleic acid were noted in patients with hemorrhagic stroke [64].…”

Section: Discussionmentioning

confidence: 94%

Assessing the causal effect of genetically predicted metabolites and metabolic pathways on stroke

Zhang,

Cao,

Zhao

et al. 2023

J Transl Med

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Background Stroke is a common neurological disorder that disproportionately affects middle-aged and elderly individuals, leading to significant disability and mortality. Recently, human blood metabolites have been discovered to be useful in unraveling the underlying biological mechanisms of neurological disorders. Therefore, we aimed to evaluate the causal relationship between human blood metabolites and susceptibility to stroke. Methods Summary data from genome-wide association studies (GWASs) of serum metabolites and stroke and its subtypes were obtained separately. A total of 486 serum metabolites were used as the exposure. Simultaneously, 11 different stroke phenotypes were set as the outcomes, including any stroke (AS), any ischemic stroke (AIS), large artery stroke (LAS), cardioembolic stroke (CES), small vessel stroke (SVS), lacunar stroke (LS), white matter hyperintensities (WMH), intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), transient ischemic attack (TIA), and brain microbleeds (BMB). A two‐sample Mendelian randomization (MR) study was conducted to investigate the causal effects of serum metabolites on stroke and its subtypes. The inverse variance-weighted MR analyses were conducted as causal estimates, accompanied by a series of sensitivity analyses to evaluate the robustness of the results. Furthermore, a reverse MR analysis was conducted to assess the potential for reverse causation. Additionally, metabolic pathway analysis was performed using the web-based MetOrigin. Results After correcting for the false discovery rate (FDR), MR analysis results revealed remarkable causative associations with 25 metabolites. Further sensitivity analyses confirmed that only four causative associations involving three specific metabolites passed all sensitivity tests, namely ADpSGEGDFXAEGGGVR* for AS (OR: 1.599, 95% CI 1.283–1.993, p = 2.92 × 10−5) and AIS (OR: 1.776, 95% CI 1.380–2.285, p = 8.05 × 10−6), 1-linoleoylglycerophosph-oethanolamine* for LAS (OR: 0.198, 95% CI 0.091–0.428, p = 3.92 × 10−5), and gamma-glutamylmethionine* for SAH (OR: 3.251, 95% CI 1.876–5.635, p = 2.66 × 10−5), thereby demonstrating a high degree of stability. Moreover, eight causative associations involving seven other metabolites passed both sensitivity tests and were considered robust. The association result of one metabolite (glutamate for LAS) was considered non-robust. As for the remaining metabolites, we speculate that they may potentially possess underlying causal relationships. Notably, no common metabolites emerged from the reverse MR analysis. Moreover, after FDR correction, metabolic pathway analysis identified 40 significant pathways across 11 stroke phenotypes. Conclusions The identified metabolites and their associated metabolic pathways are promising circulating metabolic biomarkers, holding potential for their application in stroke screening and preventive strategies within clinical settings.

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Section: Discussionmentioning

confidence: 94%

Assessing the causal effect of genetically predicted metabolites and metabolic pathways on stroke

Zhang,

Cao,

Zhao

et al. 2023

J Transl Med

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“…41 However, a 2023 prospective study revealed no association between TMAO levels and ischemic stroke severity or functional prognosis following reperfusion therapy. 86…”

Section: Potential Value Of Tmaomentioning

confidence: 99%

“…Moreover, a 2023 study found that elevated plasma isovaleric acid levels were negatively correlated with the severity of mild stroke and disability postreperfusion therapy for ischemic stroke. 86 Collectively, these clinical studies imply that SCFA supplementation could be beneficial for treating ischemic stroke and enhancing prognosis.…”

Section: Human Studiesmentioning

confidence: 99%

Role of gut microbiota in ischemic stroke: A narrative review of human and animal studies

Chen,

Du,

Cui

et al. 2024

Neuroprotection

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The high incidence, mortality, and disability associated with ischemic stroke pose a significant threat to human health. The intestinal microbiota significantly influences the onset, progression, and prognosis of ischemic stroke. Gut flora plays a pivotal role in brain–gut interactions. The reflection of changes in the gut and brain caused by gut microbes facilitates the investigation of early warning biomarkers and potential therapeutic targets for ischemic stroke. In this narrative review of the relationship between gut microbiota and ischemic stroke, we primarily discuss three topics, grounded in real‐world human and animal studies. First, we examined the relationship between ischemic stroke and intestinal microbiota and its metabolites, delineate the overall characteristics of intestinal microbiota dysregulation in ischemic stroke, and assess the potential clinical value, prevailing research controversies, and unique phenomena of intestinal microbiota metabolites such as trimethylamine N‐oxide and short‐chain fatty acids in ischemic stroke. Second, we explored the potential communication pathways between intestinal flora and ischemic stroke based on the brain–gut axis, encompassing metabolic pathways, immune pathways, and neural pathways. Finally, we encapsulated the factors influencing the severity of ischemic stroke via intestinal flora, the pharmacological and nonpharmacological interventions that modulate intestinal flora in treating ischemic stroke, and the current research landscape of intestinal flora in the context of ischemic stroke sequelae.

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“…The GM in uences stroke risk through various pathways, including host metabolism, immune responses, and vascular function. For instance, GM impact the production of metabolites such as short-chain fatty acids (SCFA) and trimethylamine N-oxide (TMAO), directly linked to stroke incidence [9][10][11]. However, observational studies have limitations, often overlooking key confounding factors, leading to biased results [12].…”

Section: Introductionmentioning

confidence: 99%

Investigating the Relationship Between Gut Microbiota and Ischemic Stroke: Genetic Causality and Metabolite Mediation

Ye,

Yu,

Shen

et al. 2024

Preprint

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Background The gut microbiota(GM) plays a significant role in health and disease, with numerous studies confirming its association with various diseases. This study aims to evaluate the genetic causal relationship between GM and ischemic stroke (IS), along with exploring potential blood metabolite-mediated mechanisms. Methods Utilizing two-sample Mendelian Randomization (MR) and large-scale Genome-Wide Association Studies (GWAS) data, we investigate the association between GM and IS. Bayesian Weighted MR (BWMR) is employed for validation, and genetic correlations are assessed using Bivariate Linkage Disequilibrium Score Regression (LDSC) and Genetic Analysis Incorporating Pleiotropy and Annotation (GPA). Results Our analysis using Inverse Variance Weighted (IVW) method indicates that specific microbial groups, such as genus Ruminiclostridium and order Burkholderiales, are significantly associated with IS risk. Mediation analysis suggests that metabolites like Pyruvate, Arachidonate, and HDL-related lipoproteins may mediate this relationship. Multivariate MR analysis confirms the independence of these mediating effects. Furthermore, both LDSC and GPA analyses demonstrate significant genetic correlations between GM and IS. Conclusion Through the integration of various statistical methods and GWAS data, this study provides genetic evidence supporting the causal relationship between GM and IS, uncovering potential biological mediating mechanisms. These findings enhance our understanding of the GM's role in cardiovascular and cerebrovascular diseases, offering insights into preventive and treatment strategies.

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The Prognostic Biomarkers of Plasma Trimethylamine N-Oxide and Short-Chain Fatty Acids for Recanalization Therapy in Acute Ischemic Stroke

Cited by 5 publications

References 34 publications

Assessing the causal effect of genetically predicted metabolites and metabolic pathways on stroke

Assessing the causal effect of genetically predicted metabolites and metabolic pathways on stroke

Role of gut microbiota in ischemic stroke: A narrative review of human and animal studies

Investigating the Relationship Between Gut Microbiota and Ischemic Stroke: Genetic Causality and Metabolite Mediation

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