Data Management And Sharing System of China National Clinical Research Center for Neurological Diseases

Journal：Frontiers in Neuroscience

Publication type: Original Contributions

IF(IF): 3.2

PMID: 38650617 Link To Pubmed Full text Download

The intestinal microbiota has become as a central regulator of immune responses within the gut-brain axis. Dysbiosis of the gut microbiota can lead to communication with the central nervous system via microbial metabolites, neural pathways, and endocrine and immune signaling cascades, thereby contributing to various neurological diseases and neurodegenerative disorders, including stroke, multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease (Cryan et al., 2020; Agirman et al., 2021; Margolis et al., 2021; Singh et al., 2022). Bile acids (BAs) are metabolite of intestinal microorganisms and play a crucial role in modulating gut microbiota balance, making them key players in the gut-brain axis (Wahlström et al., 2016; Cai J. W. et al., 2022). BAs are metabolized by gut microbiota into secondary bile acids, such as ursodeoxycholic acid and tauroursodeoxycholic acid (TUDCA). These acids cross the blood–brain barrier, reducing cell apoptosis, reactive oxygen species (ROS), nitric oxide (NO), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β production, exhibiting anti-apoptotic, antioxidant, and anti-inflammatory properties (Huang F. et al., 2022; Khalaf et al., 2022). Abnormal BA metabolism leads to gut microbiota dysbiosis, resulting in immune cell abnormalities, such as T cells, B cells, lymphocytes, and white blood cell interleukins, impacting the prognosis of stroke patients (Arya and Hu, 2018). Moreover, BAs also influence lipid metabolism and are central in regulating atherosclerosis through interactions with the intestinal microbiota (Jonsson and Bäckhed, 2017; Cao et al., 2023). Studies have shown that decreased BA excretion is associated with atherosclerosis and an elevated risk of coronary artery disease (CAD) (Charach et al., 2020). Additionally, a lower total bile acid (TBA) level has been independently associated with the severity of coronary lesions in patients with confirmed or suspected CAD (Li et al., 2020). Epidemiological investigations have revealed a negative association between serum TBA levels and mortality in patients with acute ischemic stroke (AIS) (Huang L. L. et al., 2022). In the context of hemorrhagic stroke, an elevated serum TBA level has shown potential associations with reduced hematoma size at the time of intracerebral hemorrhage and a better prognosis (Wang et al., 2018). These findings suggest that the BA levels may serve as prognostic indicator in stroke patients. However, no study to date has examined the relationship between serum TBA levels and disability or poor functional outcomes in patients with AIS or transient ischemic attack (TIA). Furthermore, the associations between TBA levels and disability as well as poor functional outcomes have not been explored based on stroke etiology. In this study, we investigate the relationship between the baseline serum TBA level and the clinical prognosis in patients with AIS or TIA as well as the significance of TBA in the different Trial of Org 10,172 in Acute Stroke Treatment (TOAST) subtypes using data from the Third National Stroke Registry (CNSR-III).

Patients were categorized into four groups (Q1, <2.1umol/L; Q2, 2.1–3.7 umol/L; Q3, 3.7–6.1 umol/L; Q4, ≥6.1 umol/L) based on quartiles of TBA levels on admission. Q1 was designated as low, and Q4 as high. Continuous variables underwent normality analysis using the Kolmogorov–Smirnov test. They were summarized as the mean (standard deviation) through one-way ANOVA when all four groups exhibited normal distribution, or as the median (interquartile range) using the Kruskal-Wallis test if one group deviated from normality. Categorical variables were compared using either the Chi-square test or Fisher’s exact probability method. Logistic regression models were used to evaluate the associations between TBA levels and disability, as well as poor functional outcomes, at 3 months and 1 year. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for serum TBA levels when categorized by quartile (using the lowest quartile as the reference) and when treated as a continuous variable (per standard deviation [SD] increase). We employed three adjusted models. Model 1 was adjusted for age and sex. Model 2 was further adjusted for body mass index, current smoking, alcohol consumption, pre-stroke mRS score, TOAST classification, hypertension, diabetes, dyslipidemia, coronary heart disease, and previous stroke. Model 3 was further adjusted for antiplatelet agents, anticoagulant agents, eGFR, and hs-CRP. To visualize potential nonlinear associations of serum TBA with disability and poor functional outcomes, we constructed restricted cubic splines with three knots at the 10th, 50th, and 90th percentiles. Stratified analyses were performed in TOAST subgroups. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, United States) and R software version 4.1.3 (R Foundation for Statistical Computing, Vienna, Austria). A two-tailed p-value <0.05 was considered statistically significant.