Altered Gut Microbiome and the Risk of Ischemic Stroke - an Umbrella Meta-Analysis
Gaurav Sudhir1, Devansh Gupta2, Aishah Khan1, Sarayu Devabhaktuni3, Sindu Mukesh4, Aakash Baskar5, Arpita Bhriguvanshi6, Rohan Arora7, Urvish Patel8, Kogulavadanan Arumaithurai9
1Kasturba Medical College, 2Smt. Kashibai Navale Medical College and General Hospital, 3Dr. PSI Medical College, 4Liaquat University of Medical and Health Sciences, 5K.A.P. Viswanatham Govt Medical College, 6Department of Child Neurology, Jersey Shore University Medical Center, 7Department of Neurology, LIJ Forest Hills, Zucker School of Medicine at Hofstra/ Northwell Health, 8Icahn School of Medicine At Mount Sinai/ Creighton University, 9Mayo Clinic Health System
Objective:
To comprehensively analyze the association between gut-microbiota-produced trimethylamine-N-oxide (TMAO) and the risk of ischemic stroke.
Background:
Globally, stroke is the second leading cause of death and the third leading cause of death and disability combined. Gut bacteria dynamically communicate with the host along the bidirectional 'microbiota-gut-brain-axis'(MGBA) to regulate the immune, metabolic, and nervous systems. Gut microbiota dysbiosis can alter MGBA, which has been linked to adverse health outcomes. Gut bacteria metabolize certain nutrients to trimethylamine(TMA), which the liver converts to TMAO. An altered MGBA can manifest as increased plasma TMAO levels. Several studies suggest a positive association between elevated TMAO levels and an increased risk of disease including ischemic stroke. We sought to determine if TMAO concentration reliably predicts stroke risk conclusively.
Design/Methods:
We conducted an umbrella meta-analysis of meta-analyses from observational studies published in the last 10 years using PRISMA guidelines in PubMed. Using RevMan 5.4, we performed an inverse variance random effects model to calculate log (odds ratio[OR]) and converted it to pooled OR and 95% confidence interval(CI) to obtain a forest plot keeping alpha criteria 0.05. Heterogeneity and risk of bias assessment were assessed.
Results:
An umbrella meta-analysis of the included studies (n=36,958) examining the association between TMAO and stroke risk revealed a statistically significant association. Higher plasma TMAO was associated with 76% elevated risk of ischemic stroke [pooled-OR: 1.76 (95%CI 1.14-2.13, p=0.01) in comparison to those with a normal level. There was no significant heterogeneity (I2=0%, p=0.84) between the studies. There was a moderate risk of bias for overall studies using Newcastle-Ottawa Scale.
Conclusions:
Our study confirms a strong association between elevated TMAO, a gut microbe-dependent metabolite, and increased stroke risk. This finding positions TMAO as a potential biomarker for stroke risk stratification and highlights the need to investigate targeted interventions aimed at modulating gut microbiota to lessen cerebrovascular risk.
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