Lipid metabolism disorders can cause cholesterol overload leading to excessive deposition of lipid substances, such as low-density lipoprotein cholesterol (LDL-C), within the intima of the large and medium-sized arteries, which is considered the culprit of atherosclerosis incidence and the main risk factor of coronary heart disease, cerebral infarction and other cardiovascular and cerebrovascular diseases16,30−32. Studies have shown that excessive cholesterol in human body can convertes into bile acids and finally be discharged from feces in the form of bile salts30,33,34. Large amounts of bile acid excretion can prevent atherosclerosis incidence, while the reduction can reversely lead to increased risk of atherosclerosis and coronary heart disease19,35,36. UDCA facilitates to prevent the occurrence of atherosclerosis and promote plaque regression with dissolved cholesterol crystals37. Gideon et al.21 studied into in-hospital bile acid excretion in 68 men and 35 women admitted to hospital between 1996 and 1998 for chest pain and suspected cardiac events and followed for up to 20 years. They found a significant higher average bile acid excretion in subjects without stroke relative to those with stroke, while those with lower bile acid excretion had higher stroke incidence and mortality, suggesting that reduced bile acid excretion was also an independent risk factor for stroke incidence and death.
In many animal experiments, bile acids, in addition to being a regulator for blood lipid and cholesterol content by participating in lipid metabolism, also act as a signal molecule that activates different nuclear receptors, such as farnesoid X receptor (FXR), pregnane X receptor (PXR), vitamin D receptor (VDR), and transmembrane G protein-coupled receptor 5 (TGR5), which reduces the risk of atherosclerosis via a variety of metabolic pathways in diverse tissues20,32,33,38,39. Bile acid chelates, such as coleswelen hydrochloride, can not only reduce LDL-C content, but also decrease hypersensitive C-reactive protein (hs-CRP) content to prevent atherosclerosis incidence40.
Bile acids also show effects on anti-apoptosis and cellular protection. Andrew L. Rivard et al.24 found reduced apoptosis and improved cardiac function in rats by TUDCA administration before myocardial infarction. In a rat model of acute stroke, bile acids TUDCA presented neuroprotective effects, and the underlying mechanism was proven with the involvement of enhanced cell apoptosis in response to inhibited mitochondrial disturbance and subsequent caspase activation22. Besides, TUDCA was found to negatively regulate Nrf2 signaling pathway to decrease lipid peroxidation, inflammation and apoptosis in ACI rats41. TUDCA can not only reduce the cell apoptosis of rats with acute hemorrhagic stroke and protect the nerve from being damaged23, but also reduce the activation of glial cells in animal models of acute neuroinflammation26. Joana D. Amaral et al.25 reviewed the role of bile acids in the regulation process of apoptosis, which highlighted the anti-apoptotic effects of UDCA and TUDCA, as well as their potential application as new and alternative drugs for the treatment of apoptosis-related diseases. All these certain evidences provide some basis for the conjecture that serum TBA may have a protective effect on AIS. However, to our knowledge, the relationship between serum TBA level and the severity of AIS, in-hospital complications, and short-term prognosis in patients with AIS has not been reported.
In our study, fasting serum TBA levels were found independent of the severity of AIS on admission, and there was no significant difference in NIHSS scores among patients with different TBA concentrations (p = 0.389). Additionally, the fasting serum TBA on admission also showed no correlation with the progress of AIS symptoms or the occurrence of in-hospital complications, but a certain relationship with the 3-month clinical outcome. Following adjustments for confounding factors, such as gender, age, NIHSS score on admission, in-hospital AIS progress and occurrence of at least one complication, AF, and baseline WBC count, low serum TBA levels were still an independent risk factor for death within 3 months in patients of AIS. Patients with higher serum TBA levels on admission had a lower risk of death within 3 months, and this trend was statistically significant (P-trend < 0.05). We speculated that this may be related to the neuroprotective and anti-apoptotic effects of bile acids, yet the specific mechanism remains to be clarified.
Here, we identified an association between high fasting serum TBA levels on admission and reduced mortality within three months after stroke in patients of AIS, yet the underlying causal relationship cannot be explained as this is only a single-center retrospective study with small sample size. Although we adjusted for several covariates that might have an impact on the outcomes, there are still many possible influencing factors which have not been collected. Besides, we did not follow up the functional outcomes in patients with AIS who survived more than 3 months, thus we were unable to determine the effect of serum TBA on functional recovery. Different from other studies, our research did not observe significant correlations between serum TBA levels and serum lipid levels, including triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol27,41, while evident associations with AF incidence and WBC count, which may require further large-scale studies to determine the reliability of our conclusion.