Intracranial Aneurysm And Gut Health

Intracranial aneurysm (IA) is a pathological dilation of the intracranial artery wall, most commonly occurring in the circle of Willis, with an incidence rate of around 3% in the general population. While unruptured IAs (UIAs) are often asymptomatic, the rupture of an aneurysm leads to spontaneous subarachnoid hemorrhage (SAH), a critical condition in neurosurgery with high mortality and disability rates. Recent studies have suggested the likely role of gut microbiota in developing IAs alongside other factors such as blood metabolites, cytokines, and plasma proteins. These elements may provide novel therapeutic targets through their influence on inflammation and vascular health. Researchers utilize Mendelian randomization (MR) studies to clarify the causal connections between these factors and the development and rupture of IAs, UIAs, and SAH.

 

THE STUDY BACKGROUND

Intracranial aneurysm (IA) is a localized pathological expansion of the intracranial artery wall that primarily occurs in the circle of Willis. The incidence rate of IA in the general population is around 3%. While unruptured IAs (UIAs) are often asymptomatic, about 85% of spontaneous subarachnoid hemorrhage (SAH) cases are caused by ruptured aneurysms [1]. SAH is a critical condition in neurosurgery, with mortality rates ranging from 30% to 50%. SAH affects approximately 6.67 of 100,000 individuals globally annually [2,3]. These alarming statistics underline the importance of understanding the mechanisms underlying IA formation and rupture and developing preventive and therapeutic strategies.

Recent research has increasingly pointed toward gut microbiota and its metabolites as potential contributors to various central nervous system disorders, including stroke [4]. These studies have also indicated that gut flora could influence the development of vascular conditions. For instance, a mice study found that antibiotic treatment reduces the incidence of IAs by depleting gut microbiota. It portends that an imbalance in gut microbiota may be a high-risk factor for developing aneurysms [5]. This emerging field highlights the potential of targeting gut microbiota as a novel therapeutic approach to preventing IA and other cerebrovascular diseases.

In addition to the gut microbiota, cytokines and plasma proteins are also believed to play critical roles in the pathogenesis of IA. Cytokines are key mediators of the immune system’s inflammatory response, and chronic low-grade inflammation has been linked to an increased risk of aneurysm formation and rupture [6]. Macrophage infiltration in both ruptured and unruptured IA tissues and higher white blood cell infiltration levels in ruptured aneurysms suggest a close link between vascular inflammation and aneurysm rupture [7]. Furthermore, plasma proteins, involved in numerous biological processes and circulatory diseases, have been identified as potential biomarkers for predicting aneurysm rupture through mass spectrometry-based screening methods [8].

Given the complexity of these factors, Mendelian randomization (MR) studies offer a powerful tool to explore the causal associations between gut microbiota, other variables (blood metabolites, plasma proteins, and cytokines), and IA outcomes. MR studies use genetic variants as instrumental variables to infer causal relationships, minimizing confounding and reverse causation often present in traditional observational studies [9]. Leveraging large-scale genome-wide association study (GWAS) data, researchers are now examining the connections between these biological factors and the development of IA, UIA, and SAH to identify new therapeutic targets for preventing and treating these conditions [10].

 

THE STUDY METHOD

The study’s methodology consisted of several necessary steps aimed at investigating the causal relationships between gut microbiota, blood metabolites, cytokines, plasma proteins, and outcomes related to intracranial aneurysm (IA), unruptured intracranial aneurysm (UIA), and subarachnoid hemorrhage (SAH). First, the researchers gathered summary statistics from genome-wide association studies (GWAS) related to the gut microbiota, blood metabolites, cytokines, plasma protein quantitative trait loci (QTLs), and the diseases of interest. They then conducted a large-scale two-sample Mendelian randomization (MR) analysis to explore the effects of these factors on the disease outcomes.

For gut microbiota, the researchers obtained data from the MiBioGen consortium, which analyzed genetic variations linked to gut microbiome abundance in over 18,000 participants. Data on cytokines and growth factors came from a GWAS that included 8,293 European individuals. Additionally, the researchers gathered data on IA, UIA, and SAH from a cross-ethnic study involving 10,754 cases and 306,882 controls. In contrast, pQTL data for plasma proteins were sourced from a survey that measured 2,994 proteins in 3,301 European participants.

To ensure the reliability of their analysis, the researchers followed specific guidelines when selecting instrumental variables (IVs). These guidelines required IVs to be associated with exposure factors unrelated to the outcome variables and free from confounding influences. They excluded single nucleotide polymorphisms (SNPs) that were too similar to each other to maintain data quality. The MR analysis was performed using specialized R packages, with the inverse-variance weighted (IVW) model as the primary approach. They also conducted additional sensitivity analyses to check for potential biases and ensure the accuracy of their findings.

 

ANALYSIS

The research analysis employed a robust Mendelian randomization (MR) approach to examine the relationship between gut microbiota, blood metabolites, cytokines, plasma proteins, and the outcomes of intracranial aneurysm (IA), unruptured intracranial aneurysm (UIA), and subarachnoid hemorrhage (SAH). Using summary statistics from large-scale genome-wide association studies (GWAS), the study conducted a two-sample MR analysis to ensure the validity of the selected instrumental variables (IVs) through strict adherence to established principles. The primary analysis utilized the inverse-variance weighted (IVW) model for estimating causal effects. Various sensitivity analyses complemented the study’s analyses to test for directional pleiotropy and the robustness of findings. Additionally, the proportion of outcome variation explained by the IVs was quantified. F-statistics were also calculated to evaluate IV strength. Through this comprehensive analysis, the study aimed to uncover significant causal associations that could inform future therapeutic targets for IA, UIA, and SAH.

 

RESULTS

• Causal Effects of Gut Microbiota on Intracranial Aneurysm (IA), Unruptured Intracranial Aneurysm (UIA), and Subarachnoid Hemorrhage (SAH)

• • Study Cohort: Analysis conducted on 211 taxa within the MiBioGen consortium, using genetic variations as instrumental variables (IVs) ranging from 3 to 17 single nucleotide polymorphisms (SNPs).

• Findings:

• Gut Microbiomes Identified:

• • • Intracranial Aneurysm (IA): 5 microbiomes
    • Unruptured Intracranial Aneurysm (UIA): 8 microbiomes
    • Subarachnoid Hemorrhage (SAH): 5 microbiomes

     – Key Genus: 

        –  Bilophila: Exhibited adverse causal effects across all three disease types:

         –  IA: p = 0.002, Effect size (b) = -0.43

         –  UIA: p < 0.001, Effect size (b) = -0.63

         –  SAH: p = 0.02, Effect size (b) = -1.08

     – Other Significant Findings:

        – Clostridiaceae: Negative causal effects on IA (b = -0.54) and UIA (b = -0.42).

       – Porphyromonadaceae: Negative causal effects on IA (b = -0.63) and UIA (b = -0.67).

        – Streptococcus: Positive causal effects on IA (b = 0.31) and SAH (b = 0.39).

• Causal Effects of Blood Metabolites on IA, UIA, and SAH

• • Study Cohort: Analysis of 468 blood metabolites using MR analysis.
  • Findings:

• Serum Metabolites Identified:

• • • • IA: 18 metabolites
      • UIA: 20 metabolites
      • SAH: 17 metabolites

• Key Metabolite:

• • • 1-Palmitoylglycerophosphoethanolamine: Showed a positive causal relationship with all three conditions:
      • IA: b = 0.79
      • UIA: b = 1.55
      • SAH: b = 1.42
  • Other Notable Metabolites:
    • 3-Indoxyl sulfate: Positive effect on IA and SAH.
    • 1-Linoleoylglycerophosphoethanolamine, 1-Arachidonoylglycerophosphocholine, Isovalerylcarnitine, and 1-Stearoylglycerophosphoethanolamine: Various effects noted, with some negative associations.
    • Pyridoxate, Androsterone sulfate, and 7-alpha-hydroxy-3-oxo-4-cholestenoate had positive effects, primarily on IA and UIA.

• Causal Effects of Cytokines on IA, UIA, and SAH

• • Study Cohort: Included 28 cytokines, with SNPs ranging from 3 to 18 for each inflammatory factor.

• Findings:

• • Key Cytokines:
    • Interleukin-6 (IL-6): Causal effect on UIA (b = 0.73, p = 0.03), indicating higher levels increase risk.
    • Monokine Induced by Gamma Interferon (MIG): Causal effect on SAH (b = -0.27, p = 0.02), indicating higher levels reduce risk.

• Causal Effects of Plasma Proteome on IA, UIA, and SAH

• Study Cohort: Analysis conducted on 2994 plasma proteins, with results corrected for false positives using the Benjamini-Hochberg method.
• Findings: Specific outcomes and relationships for individual proteins were noted, providing insights into their potential roles in these conditions.

This summary clarifies the results, emphasizes significant findings, and explains the research implications.

 

DISCUSSION

The discussion section of this research highlights the application of Mendelian Randomization (MR) to explore associations between gut microbiota, blood metabolites, cytokines, and plasma proteome with intracranial aneurysms (IA), subarachnoid hemorrhage (SAH), and unruptured intracranial aneurysms (UIA). The study identifies several gut microbiota species as having causal effects on these conditions, reinforcing the growing evidence that environmental factors, such as gut microbiota, play a significant role in IA pathophysiology compared to genetic factors [27,28]. Gut microbiota can influence IA formation and rupture by regulating local inflammation and affecting blood pressure [29]. These findings align with previous research demonstrating differential microbial composition between UIA patients and controls [30]. However, further research is required to understand the exact mechanisms of microbiota action on aneurysms.

The study reveals that certain bacterial families and genera, like Prevotella7 and Clostridiaceae1, have varying roles in aneurysm development [31]. These results are consistent with findings from other studies, which indicate that Porphyromonadaceae and Bilophila are protective against both SAH and UIA [32]. Additionally, the abundance of Streptococcaceae is associated with a higher risk of IA and UIA, highlighting the potential clinical relevance of considering microbiota in aneurysm management [33]. 

Hypertension is a well-established risk factor for SAH [34], and research linking gut microbiota to hypertension suggests a potential connection. For example, the genus Eubacterium xylanophilum is negatively associated with SAH, possibly due to its influence on blood pressure [35]. Interestingly, the genus Intestinimonas is negatively associated with ischemic stroke but increases the risk of SAH, underscoring the complexity of these microbial interactions.

Moreover, the study identifies protective factors like Lachnospiraceae for UIA, which might relate to metabolic factors such as body mass index (BMI) [37,38]. Positive associations are also found between the genus Victivallis and increased risks for UIA and SAH, alongside known risk factors such as smoking and hyperhomocysteinemia [40,41]. Additionally, the researchers report novel associations between specific plasma metabolites and IA, UIA, and SAH, including identifying arachidonic acid-class substances as potential protective factors due to their anti-inflammatory properties [44,45].

 

In summary, this study contributes to understanding the role of gut flora and metabolites in the pathogenesis of intracranial aneurysms and related conditions. While certain bacterial species appear protective, others increase the risk, illustrating the intricate relationship between gut microbiota and vascular diseases. Further research is necessary to clarify the underlying mechanisms and to explore potential clinical applications, such as targeted microbial therapies to reduce IA risk.

 

STUDY LIMITATIONS

• Lack of Comprehensive Mechanistic Insight

• The specific mechanisms by which gut microbiota influence intracranial aneurysms (IA), unruptured intracranial aneurysms (UIA), and subarachnoid hemorrhage (SAH) remain unclear, requiring further research.

• Limited Understanding of Antibiotic Impact 

• Although experts suggest that antibiotics could reduce the incidence of IA, the precise effects on gut microbiota and the risk of IA and SAH remain ambiguous.

• Contradictory Findings  

• Some findings, such as the association of 3-indoxyl sulfate with reduced IA and SAH risk, contradict prior research, highlighting potential inconsistencies.

• Unclear Associations in Blood Metabolites 

• For the first time, several newly identified plasma metabolites related to IA, UIA, and SAH are being reported, and their exact roles remain uncertain.

1. Complexities of Gut Microbiota and Disease Interaction 

• While specific gut microbiota species are implicated in aneurysm risk and protection, the broader, complex interactions between microbiota, inflammation, and disease development are not fully understood.

1. Metabolite Associations with Dual Impacts  

• Some metabolites, like 1-palmitoleoylglycerophosphocholine, exhibit dual roles—protective in one condition and a risk factor in another, complicating interpretation.

1. Limited Generalizability  

• The findings are based on specific population groups, and applying them to broader or more diverse populations may be challenging.

1. Insufficient Data on Causal Relationships  

• Although experts have linked gut microbiota imbalance to IA, a definitive causal link has yet to be established, impeding further clinical application.

1. Confounding Factors in Risk Assessment  

• Various confounding factors, such as hypertension, smoking, and genetic disorders, complicate the assessment of gut microbiota and metabolite influence on aneurysm development.

 

1. Need for Further Validation  

• Many associations identified in this study, particularly regarding metabolites and microbiota, require further validation in more extensive, diverse cohort studies.

 

CONCLUSION

This study employed a Mendelian Randomization (MR) approach to explore the causal relationships between gut microbiota, blood metabolites, cytokines, plasma proteome, and the risk of intracranial aneurysms (IA), unruptured intracranial aneurysms (UIA), and subarachnoid hemorrhage (SAH). The analysis identified numerous potential biomarkers associated with these conditions. These findings offer valuable insights for assessing disease risk and serve as a foundation for future research on IA, UIA, and SAH.

 

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