Skip to main content
NCBI home page
Medicine logoLink to Medicine
. 2025 Jul 4;104(27):e43062. doi: 10.1097/MD.0000000000043062

Mendelian randomization analysis reveals causal links between gut microbiota, serum metabolites, and aneurysm risk

Chun Xue a, Li Feng b, Shuaishuai Xi c, Kaiyuan Li d, Yuanmin Pei c,*
PMCID: PMC12237332  PMID: 40629643

Abstract

The causal relationships between gut microbiota, serum metabolites, and aneurysms remain unclear. This study employed Mendelian randomization to investigate potential causal links between gut microbiota, serum metabolites, and the risk of various types of aneurysms. Data on gut microbiota, serum metabolites, and aneurysms were obtained from genome-wide association studies. Gut microbiota and serum metabolites were analyzed as exposure factors, while cerebral aneurysms, aortic aneurysms, and thoracic aortic aneurysms were evaluated as outcome variables. Inverse-variance weighted (IVW) analysis served as the primary analytical method, complemented by sensitivity analyses to assess pleiotropy and enhance robustness. IVW analysis identified 8, 5, and 9 gut microbiota taxa as causally associated with cerebral aneurysm, thoracic aortic aneurysm, and aortic aneurysm, respectively (IVW, all P < .05). Notably, Bifidobacterium exhibited a potentially protective effect against cerebral and aortic aneurysms. Additionally, 3 serum metabolites were found to have a potential causal relationship with aortic aneurysms after false discovery rate correction. Sensitivity analyses confirmed the robustness of the IVW findings. This study suggests that gut microbiota and serum metabolites may influence aneurysm risk, offering novel insights for the clinical diagnosis and treatment of aneurysms.

Keywords: aneurysms, gut microbiota, Mendelian randomization, serum metabolites, single nucleotide polymorphisms

1. Introduction

The aneurysm is characterized by a localized or diffuse dilation or bulging of the arterial wall, arising from various etiologies. The most significant risk associated with an aneurysm is rupture, which can result in severe internal bleeding or potentially life-threatening complications. The incidence of aneurysms varies across geographic regions and populations, with cerebral aneurysms, aortic aneurysms, and thoracoabdominal aortic aneurysms being the most commonly observed types.[1] The global prevalence of cerebral aneurysms is estimated to range from approximately 0.7% to 7%. In contrast, the prevalence of abdominal aortic aneurysms varies by country and region, ranging from approximately 1% to 5% in the United States. Thoracic aortic aneurysms are comparatively less common.[2–5]

The gut microbiota plays a critical role not only in food digestion and nutrient absorption but also in the body’s metabolic processes.[6,7] Increasing evidence suggests that an imbalanced gut microbiota may be associated with various health issues, including inflammatory bowel disease, irritable bowel syndrome, depression, and obesity. These findings highlight the gut microbiota’s close involvement in complex immune regulation, inflammatory responses, and the brain–gut axis, among other physiological functions.[8–11]

Serum metabolites are small molecules that serve as intermediate or final products of metabolic reactions. Their levels are influenced by various factors, including genetics, diet, and the gut microbiota.[12–14] The knowledge of the causal role of serum metabolites in the etiology of disease can provide easily manageable points of intervention for treatment.[15]

Available studies have shown that chronic inflammatory factors and serum metabolites, such as short-chain fatty acids, may indirectly influence aneurysm formation.[16–18] Among the many metabolites produced by the gut microbiota, short-chain fatty acids, including acetic, propionic, and butyric acids, play a role in immune regulation and may inhibit the secretion of tumor necrosis factor and interleukin-6 by attenuating inflammatory responses. While inflammation is recognized as a key contributor to aneurysm formation, conclusive evidence of a direct causal relationship between gut microbiota, serum metabolites, and aneurysm formation remains lacking.[19–22]

Mendelian randomization (MR) studies utilize single nucleotide polymorphism (SNP) of exposure factors as instrumental variables. The random assortment of SNP combinations during the formation of a fertilized egg can influence the outcome measures of interest. This random allocation is akin to the random assignment in clinical trials, which allows MR to be regarded as a natural, controlled trial for investigating causal relationships between exposure factors and outcomes. This study employed MR analysis.[23,24]

The study screened gut microbiota and serum metabolites with significant genetic variation to explore their causal relationships with 3 common types of aneurysms: cerebral aneurysm, aortic aneurysm, and thoracic aortic aneurysm. The findings further elucidate the gut microbiota and serum metabolites associated with aneurysm formation, offering new insights that may inform future clinical diagnosis and treatment strategies for aneurysms (Fig. 1).

Figure 1.

Figure 1.

Open in a new tab

Diagram of the causal relationship between gut microbiota, serum metabolites, and the risk of aneurysm development.

2. Materials and methods

2.1. Study design

The study employed two-sample MR to investigate the causal relationship between gut microbiota and aneurysms, adhering to the 3-core instrumental variable assumptions of MR studies: the genetic variants selected as instrumental variables are associated with the exposure factor (gut microbiota). The genetic variants are not associated with confounding factors. The genetic variants are not directly associated with aneurysms. As this study utilized publicly available published data, no additional ethical approval or consent was required (Fig. 2A).

Figure 2.

Figure 2.

Open in a new tab

(A) Diagram for MR. MR is based on 3 hypotheses: (1) genetic variation selected as an instrumental variable is associated with the exposure factor gut microbiota. (2) Genetic variation is not associated with confounding factors. (3) Genetic variation is not associated with aneurysms. (B) Workflow of the study. MR = Mendelian randomization.

2.2. Date sources

2.2.1. Exposure sources and genetic instrument selection

Gut microbiota data were downloaded from the MiBioGen website. A total of 18,340 16S rRNA gene sequencing profiles and genotyping data were collected from 18,340 subjects in 11 countries, including Asia and Europe, to identify genetic loci that influence the relative abundance or presence of microbial taxa. Considering that few SNPs loci with P < 5 × 10-8 were available for gut microbiota, SNPs loci with P < 1 × 10-5 were selected, and the loci obtained from the screening were used as instrumental variables in place of the clinical risk exposure factor gut microbiota.[25,26] Data from SNPs with chained unbalanced aggregates were subsequently removed, with removal conditioned on linkage disequilibrium (r2 < 0.001, distance = 10,000 kb), SNPs with F-statistics < 10 were excluded to minimize errors due to data bias. Serum metabolite data were downloaded from the genome-wide association studies data, and a total of 1400 metabolite-associated exposures were collected, and SNPs were screened based on P < 5 × 10-6, with removal conditioned on linkage disequilibrium (r2 < 0.001, distance = 10,000 kb). At the same time, SNPs with F-statistics < 10 were excluded.[27] The studies included in our analysis were approved by the relevant institutional review boards, and participants signed informed consent (Fig. 2B).

2.2.2. Outcome sources

Datasets for cerebral aneurysm (ebi-a-GCST90018815; 945 cases and 472,738 controls), thoracic aortic aneurysms (ebi-a-GCST90027266; 1351 cases and 18,295 controls), and aortic aneurysm (ebi-a-GCST90018563; 1155 cases and 173,601 controls) were obtained from the genome-wide association studies database (Table 1).

Table 1.

Source of GWAS data for all types of aneurysms.

Outcome Year Author Participants Number of SNPs Web source if publicly
Cerebral aneurysm
(ebi-a-GCST90018815)		 2021 Sakaue S
(PMID: 34594039)		 473,683 individuals
(945 use cases and 472,738 controls) of
European ancestry		 24,191,145 https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST90018815/
(Access time: October 22, 2023)
Aortic aneurysm
(ebi-a-GCST90018783)		 2021 Sakaue S
(PMID:
34594039)		 479,194 individuals
(3230 use cases and 475,964 controls) of
European ancestry		 24,191,825 https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST90018783/
(Access time: October 22, 2023)
Thoracic aortic aneurysms
(ebi-a-GCST90027266)		 2021 Roychowdhury T
(PMID:
34265237)		 19,646 individuals
(1351 cases and 18,295 controls) of
European ancestry		 22,889,272 https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST90027266/
(Access time: October 22, 2023)
Open in a new tab

GWAS = genome-wide association studies.

2.3. Sensitivity analysis

Heterogeneity was assessed using the P value from the Cochran Q test. To verify the reliability of the MR analysis results, a pleiotropy test was conducted. This test utilized the intercept term from the MR-Egger method, where a P value > .05 for the intercept term indicated the absence of horizontal pleiotropy.

2.4. Statistical methods

All data analyses were performed using R software (version 4.3.1) and the R package “TwosampleMR.” Given that serum metabolites consist of 1400 species, the false discovery rate (FDR) was applied to control for erroneous rejection of the null hypothesis and to more accurately identify serum metabolites with causal relevance. Differences were considered statistically significant when the P value was < .05.[28]

3. Result

3.1. Genetic instrument variables for gut microbiota and serum metabolites

After applying the filtering conditions, 57, 150, and 67 SNPs were selected from the gut microbiota associated with cerebral aneurysm, aortic aneurysm, and thoracic aortic aneurysm, respectively, with F-statistics all > 10 (Table S1–S3, Supplemental Digital Content, https://links.lww.com/MD/P319). Similarly, 126, 104, and 153 SNPs were selected from serum metabolites associated with the 3 types of aneurysms, with F-statistics all > 10 (Table S4–S6, Supplemental Digital Content, https://links.lww.com/MD/P319).

3.2. Causal relationship between gut microbiota and cerebral aneurysm

The inverse-variance weighted (IVW) analysis results suggest that 8 gut microbiotas may have a causal relationship with cerebral aneurysm. The 6 gut microbiotas, including Burkholderiales (id.2874; OR = 1.59, 95% CI: 1.11–2.28, P = .01) and class Betaproteobacteria id.2867 (OR = 1.53, 95% CI: 1.08–2.17, P = .01), were found to be positively associated with the risk of intracranial aneurysm. The family Bifidobacteriaceae id.433 (OR = 0.73, 95% CI: 0.56–0.94, P = .01) and order Bifidobacteriales id.432 (OR = 0.73, 95% CI: 0.56–0.94, P = .01) were negatively associated with the risk of cerebral aneurysm (Fig. 3A).

Figure 3.

Figure 3.

Open in a new tab

(A–C) The results of IVW analysis of gut microbiota and cerebral aneurysms, thoracic aortic aneurysms, and aortic aneurysms, respectively.

3.3. Causal relationship between gut microbiota and thoracic aortic aneurysm

The IVW analysis results suggest that 5 gut microbiotas may have a causal relationship with thoracic aortic aneurysm. The family Peptococcaceae id.2024 (OR = 1.69, 95% CI: 1.11–2.62, P = .01) was found to be positively associated with the risk of thoracic aortic aneurysm. 4 gut microbiotas including genus Ruminococcaceae UCG013 id.11370 (OR = 0.57, 95% CI: 0.36–0.88, P = .01) and genus Dorea id.1997 (OR = 0.59, 95% CI: 0.36–0.98, P = .04) may be negatively associated with the risk of thoracic aortic aneurysm (Fig. 3B).

3.4. Causal relationship between gut microbiota and aortic aneurysm

The IVW analysis results suggest that 9 gut microbiotas may have a causal relationship with aortic aneurysm. Four gut microbiotas including genus Ruminococcaceae UCG005 id.11363 (OR = 1.43, 95% CI: 1.17–1.17, P < .01) and genus Family XIII AD3011 group id.11293 (OR = 1.28, 95% CI: 1.04–1.59, P < .01) may be positively correlated with the risk of aortic aneurysm. Five gut microbiotas including genus Ruminococcaceae NK4A214 group id.11358 (OR = 0.71, 95% CI: 0.57–0.89, P <  .01) may be negatively associated with the risk of aortic aneurysm risk (Fig. 3C).

3.5. Causal relationship between serum metabolites and aneurysms

In the MR study of serum metabolites and 3 types of aneurysms, IVW analyses identified 32, 22, and 30 serum metabolites that may have a potential causal relationship with the risk of developing intracranial aneurysms, thoracic aortic aneurysms, and aortic aneurysms, respectively (Figs. 4 and 5). Due to the large number of results analyzed, the study applied FDR correction. The results (PFDR < .05) indicated that phosphate to oleoyl-linoleoyl-glycerol (18:1–18:2) (OR = 0.69, 95% CI: 0.59–0.82, PFDR < .01) and Octadecanedioate levels (OR = 0.69, 95% CI: 0.59–0.82, PFDR < .01) may be negatively correlated with the risk of aortic aneurysm. Conversely, Oleoyl-linoleoyl-glycerol (18:1/18:2) and Octadecanedioate levels (OR = 1.36, 95% CI: 1.16–1.59, PFDR = .03) may be positively associated with the risk of aortic aneurysm.

Figure 4.

Figure 4.

Open in a new tab

(A and B) The results of IVW analysis of serum metabolites and cerebral aneurysms, thoracic aortic aneurysms respectively.

Figure 5.

Figure 5.

Open in a new tab

The results of IVW analysis of serum metabolites and aortic aneurysms.

3.6. None of the sensitivity analyses revealed any differences

The results of the heterogeneity test showed that there was no heterogeneity among the SNPs (P > .05). The results of the MR-Egger regression intercept showed that there was no horizontal multiplicity in the correlation between gut microbiota, serum metabolites and aneurysms (Tables 2 and 3). The results of leave-one-out analysis showed that there were no SNPs that had a significant impact on the effect estimate. In summary, the results of this study were relatively stable.

Table 2.

Sensitivity analyses of the causal effect of gut microbiome on aneurysms.

Outcome Exposure Test for directional horizontal pleiotropy Cochran Q test
Egger intercept SE P value Cochran Q Cochran P
Cerebral aneurysm
(id: ebi-a-GCST90018815)		 Class Betaproteobacteria id.2867 -0.02 0.04 .61 15.0 0.13
Cerebral aneurysm
(id: ebi-a-GCST90018815)		 Class Coriobacteriia id.809 -0.02 0.03 .53 7.58 0.81
Cerebral aneurysm
(id: ebi-a-GCST90018815)		 Family Bifidobacteriaceae id.433 0.011 0.03 .75 9.44 0.49
Cerebral aneurysm
(id: ebi-a-GCST90018815)		 Family Coriobacteriaceae id.811 -0.02 0.03 .53 7.58 0.81
Cerebral aneurysm
(id: ebi-a-GCST90018815)		 Genus Eggerthella id.819 -0.07 0.06 .27 9.86 0.36
Cerebral aneurysm
(id: ebi-a-GCST90018815)		 Order Bifidobacteriales id.432 0.01 0.03 .75 9.44 0.49
Cerebral aneurysm
(id: ebi-a-GCST90018815)		 Order Burkholderiales id.2874 -0.01 0.04 .93 14.2 0.11
Cerebral aneurysm
(id: ebi-a-GCST90018815)		 Order Coriobacteriales id.810 0.02 0.03 .53 7.58 0.81
Aortic aneurysm
(id: ebi-a-GCST90018783)		 Class Actinobacteria id.419 0.01 0.02 .95 20.1 0.09
Aortic aneurysm
(id: ebi-a-GCST90018783)		 Family Bifidobacteriaceae id.433 0.02 0.02 .31 8.72 0.55
Aortic aneurysm
(id: ebi-a-GCST90018783)		 Genus Anaerofilum id.2053 0.03 0.04 .44 8.32 0.50
Aortic aneurysm
(id: ebi-a-GCST90018783)		 Genus Butyricimonas id.945 0.02 0.03 .47 13.1 0.28
Aortic aneurysm
(id: ebi-a-GCST90018783)		 Genus Family XIII AD3011 group id.11293 0.03 0.04 .37 10.5 0.48
Aortic aneurysm
(id: ebi-a-GCST90018783)		 Genus Prevotella9 id.11183 -0.01 0.02 .85 8.58 0.80
Aortic aneurysm
(id: ebi-a-GCST90018783)		 Genus Ruminococcaceae NK4A214 group id.11358 0.01 0.02 .88 5.71 0.89
Aortic aneurysm
(id: ebi-a-GCST90018783)		 Genus Ruminococcaceae UCG005 id.11363 0.004 0.02 .88 12.1 0.43
Aortic aneurysm
(id: ebi-a-GCST90018783)		 Order Bifidobacteriales id.432 -0.02 0.02 .31 8.72 0.55
Thoracic aortic aneurysms
(id: ebi-a-GCST90027266)		 Family Oxalobacteraceae id.2966 -0.03 0.06 .63 6.42 0.89
Thoracic aortic aneurysms
(id: ebi-a-GCST90027266)		 Family Peptococcaceae id.2024 -0.05 0.05 .31 8.76 0.27
Thoracic aortic aneurysms
(id: ebi-a-GCST90027266)		 Genus Dorea id.1997 -0.01 0.04 .88 6.71 0.56
Thoracic aortic aneurysms
(id: ebi-a-GCST90027266)		 Genus Lachnospiraceae FCS020 group id.11314 0.01 0.03 .81 4.28 0.93
Thoracic aortic aneurysms
(id: ebi-a-GCST90027266)		 Genus Ruminococcaceae UCG013 id.11370 -0.04 0.04 .37 8.71 0.56
Open in a new tab

Table 3.

Sensitivity analyses of the causal effect of serum metabolites on aortic aneurysms.

Outcome Exposure Test for directional horizontal pleiotropy Cochran Q test
Egger intercept SE P FDR Cochran Q Cochran P
Aortic aneurysm
(id: ebi-a-GCST90018783)		 Phosphate to oleoyl-linoleoyl-glycerol (18:1–18:2) 0.01 0.03 .89 5.28 0.26
Aortic aneurysm
(id: ebi-a-GCST90018783)		 Octadecanedioate levels 0.02 0.05 .70 0.327 0.84
Aortic aneurysm
(id: ebi-a-GCST90018783)		 Oleoyl-linoleoyl-glycerol (18:1/18:2) -0.01 0.02 .57 6.61 0.25
Open in a new tab

4. Discussion

The causes of aneurysms may involve a variety of factors, the most common being lipid metabolism, bacterial infections, and hypertension. Recent studies have reported a significant association between increased arterial elastance (stiffness) and aortic aneurysm disease.[29–31] The microbiota, as an important part of the human body, may work together to participate in the multiple mechanisms described above to influence the development and progression of aneurysms.[32–35]

In this study, 8 gut microbiota taxa were found to be potentially associated with the risk of aortic aneurysm through MR analysis. Four of these microbiotas, including Ruminococcaceae UCG005 id.11363, the genus Anaerofilum id.2053, and the genus Butyricimonas id.945, showed a positive association with the risk of aneurysm. Some studies have reported that Ruminococcus species are closely linked to cholelithiasis and lipid metabolism and may inhibit inflammatory bowel damage by attenuating inflammatory responses through the TLR4/NF-κB pathway. However, whether Ruminococcaceae influence vascular diseases such as aneurysms by modulating inflammatory responses has not yet been reported.[36,37] In addition, Ruminococcaceae have been shown to reduce inflammation by modulating T cell numbers and the production of short-chain fatty acids.[38] Interestingly, Ruminococcaceae NK4A214 group id.11358 was negatively associated with the risk of aneurysms. Although Ruminococcaceae UCG005 id.11363 and Ruminococcaceae NK4A214 group id.11358 belong to the same bacterial family, they may ultimately exert different functional and ecological properties as their specific genera and groups represent different bacterial species or strains. In conjunction with the study, it was observed that Prevotella, Anaerofilum, and Butyricimonas are common anaerobic bacteria that decompose carbohydrates to produce short-chain fatty acids (e.g., acetic, propionic, and butyric acids) and alcohols (e.g., ethanol, isopropanol, and butanol). These bacteria also influence the activity of immune cells and modulate inflammatory responses. Furthermore, it has been shown that Butyricimonas can produce significant amounts of butyric acid, a short-chain fatty acid that plays a crucial role in maintaining gut health.[39] Butyric acid serves not only as an essential energy source for intestinal cells but also strengthens intestinal barrier function, exhibits anti-inflammatory properties, and contributes to regulating the balance of intestinal flora.[40,41] This study also identified a negative association between Actinobacteria and aortic aneurysms. Actinobacteria, a phylum known to produce short-chain fatty acids through the fermentation of dietary fiber, may play an anti-inflammatory role and help maintain the integrity of the intestinal lining; however, further exploration is warranted.[42] Additionally, Bifidobacteriaceae id.433 and Bifidobacteriales id.432, both common probiotics in the gastrointestinal tract, produce short-chain fatty acids that help reduce inflammatory responses, maintain an acidic gut environment, and inhibit the growth of harmful bacteria. These taxa were negatively associated with both aortic aneurysms and cerebral aneurysms. Previous studies have suggested that Bifidobacteriaceae may alleviate inflammatory bowel disease and sepsis by modulating inflammatory responses; however, no studies have yet confirmed whether these bacteria can mitigate vascular injury.[43–45]

The MR study of abdominal aortic aneurysms, 5 gut microbiotas were identified that may be strongly associated with the risk of developing abdominal aortic aneurysms. In this set of analyses, this study similarly found that Ruminococcaceae were negatively associated with the risk of abdominal aortic aneurysm. family Peptococcaceae id.2024, genus Dorea id.1997, and genus Lachnospiraceae FCS020 group id.11314 all Peptococcaceae are anaerobic and participate in a variety of metabolic pathways, including fermentation, sulphate reduction, and other complex chemical processes, and are capable of producing endotoxins that can enter the circulation and cause or exacerbate systemic inflammatory responses.[46,47] This reaction may affect the walls of the arteries, making them more susceptible to dilation and aneurysm formation. Dorea and Lachnospiraceae will be involved in fermenting dietary fiber and producing short-chain fatty acids, which are important for maintaining gut health and regulating the immune system.[48–50] Oxalobacteraceae are a subgroup of Aspergillus and are capable of breaking down oxalic acid, which is one of the influences on cardiovascular disease, so we hypothesized that it may be possible to influence the risk of abdominal aortic aneurysm through this mechanism.[51,52]

In the MR study of intracranial aneurysms, 8 gut microbiotas were identified that may be strongly associated with the risk of developing intracranial aneurysms. Interestingly, FAMILY Bifidobacteriaceae id.433 and ORDER Bifidobacteriales id.432 may not only be negatively correlated with the risk of aortic aneurysm, but also have similar results with the risk of intracranial aneurysm, and thus it is worthwhile to further explore the mechanisms involved. In addition, Eggerthella, Burkholderiales, Coriobacteriia, Coriobacteriaceae, Coriobacteriales and Betaproteobacteria were positively associated with the risk of intracranial aneurysms. The associations and distinctions between these bacteria may provide clues to their common and unique effects. Eggerthella and Coriobacteriaceae, both belonging to the order Coriobacteriia, may affect intracranial vascular stability and inflammatory states through similar mechanisms associated with lipid metabolism and hormone conversion.[19] At the same time, Betaproteobacteria and Burkholderiales show broader environmental adaptations and metabolic diversity that may affect systemic inflammation and vascular health through different pathways such as endotoxin release or other metabolites.[53] Although these bacterial groups overlap and differ taxonomically and in their metabolic functions, together they form a complex network of gut microbiota and collectively influence the risk of intracranial aneurysms through multiple mechanisms.

Phosphate to oleoyl-linoleoyl-glycerol (18:1–18:2) conversion involves the biosynthesis and modification of lipid metabolism, especially phospholipids and glycerolipids, and may be closely related to biological processes such as cell membrane synthesis and repair and signaling. Combined with MR analysis of the gut microbiota, Bifidobacteriaceae are then able to metabolize bile acids, thereby affecting bile acid cycling and lipid absorption, which are key regulators of lipid absorption and metabolism.[54–56] Meanwhile, both Bifidobacteriaceae and Phosphate to oleoyl-linoleoyl-glycerol (18:1–18:2) were negatively associated with the risk of aortic aneurysm. In addition to this, studies have identified a possible association between Octadecanedioate levels and lipid metabolism, and in conjunction with the previous MR of the gut microbiota, both Actinobacteria and Bifidobacteriaceae have been reported to be involved in the metabolic process that may involve Octadecanedioate levels.[57,58] Therefore, it can be found that the gut microbiota may influence the risk of aortic aneurysm through serum metabolites, but further experimental validation is still needed.

This study has several important limitations. First, the data used were derived exclusively from individuals of European descent, which limits the generalizability of the findings to other ethnic groups. As such, caution should be exercised when extrapolating these results to populations with different genetic backgrounds. Second, while this study represents the first application of MR to explore potential causal links between gut microbiota, serum metabolites, and aneurysms, most of the conclusions remain at a theoretical stage. Further research is necessary to confirm the specific causal relationships identified, evaluate the effectiveness of potential interventions, and address interindividual variability. Lastly, some microbial and metabolite names identified in this study are still in the preliminary or numbering phase, which hinders the full interpretation of the results and requires further clarification in future research.

The findings of this study suggest that gut microbiota and serum metabolites could serve as valuable biomarkers for aneurysm diagnosis and potential therapeutic targets. In the future, physicians may use specific microbial profiles to assess an individual’s risk for aneurysms and monitor the progression of the condition. Furthermore, modulating the abundance of certain microbes or altering their associated metabolites may present opportunities to mitigate the formation or progression of aneurysms. A more personalized approach to treatment could also be developed based on an individual’s unique microbial composition. For example, tailored dietary recommendations, lifestyle changes, or preventive treatments could be proposed based on the specific gut microbiota and metabolic profile of each patient.

5. Conclusion

This study suggests that gut microbiota and serum metabolites may play a causal role in the development of aneurysms through immune modulation and inflammatory responses. Specifically, certain gut microbiota and metabolites could serve as potential biomarkers for predicting aneurysm risk and offer new therapeutic targets. In the future, personalized treatment strategies could be designed based on an individual’s gut microbiome and metabolomic profile to mitigate the formation or progression of aneurysms.

Author contributions

Conceptualization: Li Feng, Chun Xue, Kaiyuan Li.

Data curation: Chun Xue, Shuaishuai Xi, Kaiyuan Li.

Writing – original draft: Chun Xue, Li Feng.

Writing – review & editing: Kaiyuan Li, Chun Xue, Yuanmin Pei.

Supplementary Material

Abbreviations:

FDR
false discovery rate
IVW
inverse-variance weighted
MR
Mendelian randomization
SNPs
single nucleotide polymorphisms

Publicly available de-identified data from participant studies approved by an ethical standards committee were used in this study. Therefore, no additional separate ethical approval was required for this study.

The authors have no funding and conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are publicly available.

Supplemental Digital Content is available for this article.

How to cite this article: Xue C, Feng L, Xi S, Li K, Pei Y. Mendelian randomization analysis reveals causal links between gut microbiota, serum metabolites, and aneurysm risk. Medicine 2025;104:27(e43062).

The data analyzed in this study are derived from publicly available datasets that can be downloaded from the website (https://mibiogen.gcc.rug.nl/ and https://gwas.mrcieu.ac.uk./).

Contributor Information

Chun Xue, Email: xuechun2017@163.com.

Li Feng, Email: 15689058957@163.com.

Shuaishuai Xi, Email: xssllyan@163.com.

References

  • [1].Spittell JA, Jr. Hypertension and arterial aneurysm. J Am Coll Cardiol. 1983;1(2 Pt 1):533–40. [DOI] [PubMed] [Google Scholar]
  • [2].Wiebers DO, Whisnant JP, Huston J, 3rd, et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet. 2003;362:103–10. [DOI] [PubMed] [Google Scholar]
  • [3].Nordon IM, Hinchliffe RJ, Holt PJ, Loftus IM, Thompson MM. Review of current theories for abdominal aortic aneurysm pathogenesis. Vascular. 2009;17:253–63. [DOI] [PubMed] [Google Scholar]
  • [4].Golledge J. Abdominal aortic aneurysm: update on pathogenesis and medical treatments. Nat Rev Cardiol. 2019;16:225–42. [DOI] [PubMed] [Google Scholar]
  • [5].Brown RD, Jr., Broderick JP. Unruptured intracranial aneurysms: epidemiology, natural history, management options, and familial screening. Lancet Neurol. 2014;13:393–404. [DOI] [PubMed] [Google Scholar]
  • [6].Hills RD, Jr., Pontefract BA, Mishcon HR, Black CA, Sutton SC, Theberge CR. Gut Microbiome: profound implications for diet and disease. Nutrients. 2019;11:1613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Adak A, Khan MR. An insight into gut microbiota and its functionalities. Cell Mol Life Sci. 2019;76:473–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [8].Hu W, Kong X, Wang H, Li Y, Luo Y. Ischemic stroke and intestinal flora: an insight into brain-gut axis. Eur J Med Res. 2022;27:73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Zou X, Wang L, Xiao L, Wang S, Zhang L. Gut microbes in cerebrovascular diseases: Gut flora imbalance, potential impact mechanisms and promising treatment strategies. Front Immunol. 2022;13:975921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Canakis A, Haroon M, Weber HC. Irritable bowel syndrome and gut microbiota. Curr Opin Endocrinol Diabetes Obes. 2020;27:28–35. [DOI] [PubMed] [Google Scholar]
  • [11].Mayer EA, Nance K, Chen S. The gut-brain axis. Annu Rev Med. 2022;73:439–53. [DOI] [PubMed] [Google Scholar]
  • [12].Bar N, Korem T, Weissbrod O, et al. A reference map of potential determinants for the human serum metabolome. Nature. 2020;588:135–40. [DOI] [PubMed] [Google Scholar]
  • [13].Lee WJ, Hase K. Gut microbiota-generated metabolites in animal health and disease. Nat Chem Biol. 2014;10:416–24. [DOI] [PubMed] [Google Scholar]
  • [14].Pietzner M, Stewart ID, Raffler J, et al. Plasma metabolites to profile pathways in noncommunicable disease multimorbidity. Nat Med. 2021;27:471–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Long T, Hicks M, Yu HC, et al. Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites. Nat Genet. 2017;49:568–78. [DOI] [PubMed] [Google Scholar]
  • [16].Sakalihasan N, Limet R, Defawe OD. Abdominal aortic aneurysm. Lancet. 2005;365:1577–89. [DOI] [PubMed] [Google Scholar]
  • [17].Nordon IM, Hinchliffe RJ, Loftus IM, Thompson MM. Pathophysiology and epidemiology of abdominal aortic aneurysms. Nat Rev Cardiol. 2011;8:92–102. [DOI] [PubMed] [Google Scholar]
  • [18].Shimada K, Furukawa H, Wada K, et al. Protective role of peroxisome proliferator-activated receptor-gamma in the development of intracranial aneurysm rupture. Stroke. 2015;46:1664–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014;157:121–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol. 2016;16:341–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].Daryabor G, Atashzar MR, Kabelitz D, Meri S, Kalantar K. The effects of type 2 diabetes mellitus on organ metabolism and the immune system. Front Immunol. 2020;11:1582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].He M, Wang W, He Q, Dai H, Han J, Cui W. Genetic causal association between the gut microbiome and intracranial aneurysm and subarachnoid hemorrhage: a two-sample mendelian randomization study. Neurol Ther. 2023;12:1695–707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Thanassoulis G, O’Donnell CJ. Mendelian randomization: nature’s randomized trial in the post-genome era. JAMA. 2009;301:2386–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Ference BA. How to use Mendelian randomization to anticipate the results of randomized trials. Eur Heart J. 2018;39:360–2. [DOI] [PubMed] [Google Scholar]
  • [25].Ma J, Li J, Jin C, et al. Association of gut microbiome and primary liver cancer: a two-sample Mendelian randomization and case-control study. Liver Int. 2023;43:221–33. [DOI] [PubMed] [Google Scholar]
  • [26].Liu B, Ye D, Yang H, et al. Assessing the relationship between gut microbiota and irritable bowel syndrome: a two-sample Mendelian randomization analysis. BMC Gastroenterol. 2023;23:150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Chen Y, Lu T, Pettersson-Kymmer U, et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nat Genet. 2023;55:44–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Chen L, Yang H, Li H, He C, Yang L, Lv G. Insights into modifiable risk factors of cholelithiasis: a Mendelian randomization study. Hepatology. 2022;75:785–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Astrom Malm I, De Basso R, Blomstrand P, Bjarnegard N. Increased arterial stiffness in males with abdominal aortic aneurysm. Clin Physiol Funct Imaging. 2021;41:68–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [30].Moulakakis KG, Pitros CF, Theodosopoulos IT, et al. Arterial stiffness and aortic aneurysmal disease - A narrative review. Vasc Health Risk Manag. 2024;20:47–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Sonaglioni A, Baravelli M, Lombardo M, et al. Ventricular-arterial coupling in centenarians without cardiovascular diseases. Aging Clin Exp Res. 2018;30:367–73. [DOI] [PubMed] [Google Scholar]
  • [32].Tian Z, Zhang Y, Zheng Z, et al. Gut microbiome dysbiosis contributes to abdominal aortic aneurysm by promoting neutrophil extracellular trap formation. Cell Host Microbe. 2022;30:1450–63.e8. [DOI] [PubMed] [Google Scholar]
  • [33].Xie J, Lu W, Zhong L, et al. Alterations in gut microbiota of abdominal aortic aneurysm mice. BMC Cardiovasc Disord. 2020;20:32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [34].Shinohara R, Nakashima H, Emoto T, et al. Gut microbiota influence the development of abdominal aortic aneurysm by suppressing macrophage accumulation in mice. Hypertension. 2022;79:2821–9. [DOI] [PubMed] [Google Scholar]
  • [35].Kawabata S, Takagaki M, Nakamura H, et al. Dysbiosis of gut microbiome is associated with rupture of cerebral aneurysms. Stroke. 2022;53:895–903. [DOI] [PubMed] [Google Scholar]
  • [36].Liang J, Kou S, Chen C, et al. Effects of Clostridium butyricum on growth performance, metabonomics and intestinal microbial differences of weaned piglets. BMC Microbiol. 2021;21:85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [37].Li W, Ren A, Qin Q, et al. Causal associations between human gut microbiota and cholelithiasis: a mendelian randomization study. Front Cell Infect Microbiol. 2023;13:1169119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [38].van den Munckhof ICL, Kurilshikov A, Ter Horst R, et al. Role of gut microbiota in chronic low-grade inflammation as potential driver for atherosclerotic cardiovascular disease: a systematic review of human studies. Obes Rev. 2018;19:1719–34. [DOI] [PubMed] [Google Scholar]
  • [39].Louis P, Flint HJ. Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiol Lett. 2009;294:1–8. [DOI] [PubMed] [Google Scholar]
  • [40].Berni Canani R, Di Costanzo M, Leone L. The epigenetic effects of butyrate: potential therapeutic implications for clinical practice. Clin Epigenetics. 2012;4:4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Rios-Covian D, Ruas-Madiedo P, Margolles A, Gueimonde M, de Los Reyes-Gavilan CG, Salazar N. Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol. 2016;7:185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Duan M, Han ZH, Huang T, Yang Y, Huang B. Characterization of gut microbiota and short-chain fatty acid in breastfed infants with or without breast milk jaundice. Lett Appl Microbiol. 2021;72:60–7. [DOI] [PubMed] [Google Scholar]
  • [43].Hong CJ, Chen SY, Hsu YH, Yen GC. Protective effect of fermented okara on the regulation of inflammation, the gut microbiota, and SCFAs production in rats with TNBS-induced colitis. Food Res Int. 2022;157:111390. [DOI] [PubMed] [Google Scholar]
  • [44].Fang H, Fang M, Wang Y, et al. Indole-3-Propionic acid as a potential therapeutic agent for sepsis-induced gut microbiota disturbance. Microbiol Spectr. 2022;10:e0012522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [45].Ma F, Sun M, Song Y, et al. Lactiplantibacillus plantarum-12 alleviates inflammation and colon cancer symptoms in AOM/DSS-Treated mice through modulating the intestinal microbiome and metabolome. Nutrients. 2022;14:1916. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [46].Monk JM, Lepp D, Zhang CP, et al. Diets enriched with cranberry beans alter the microbiota and mitigate colitis severity and associated inflammation. J Nutr Biochem. 2016;28:129–39. [DOI] [PubMed] [Google Scholar]
  • [47].Kim S, Choi S, Dutta M, et al. Pregnane X receptor exacerbates nonalcoholic fatty liver disease accompanied by obesity- and inflammation-prone gut microbiome signature. Biochem Pharmacol. 2021;193:114698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [48].Gao J, Guo X, Wei W, et al. The association of fried meat consumption with the gut microbiota and fecal metabolites and its impact on glucose homoeostasis, intestinal endotoxin levels, and systemic inflammation: a randomized controlled-feeding trial. Diabetes Care. 2021;44:1970–9. [DOI] [PubMed] [Google Scholar]
  • [49].Wang X, Wang Z, Cao J, Dong Y, Chen Y. Gut microbiota-derived metabolites mediate the neuroprotective effect of melatonin in cognitive impairment induced by sleep deprivation. Microbiome. 2023;11:17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [50].Deng K, Shuai M, Zhang Z, et al. Temporal relationship among adiposity, gut microbiota, and insulin resistance in a longitudinal human cohort. BMC Med. 2022;20:171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [51].Crivelli JJ, Mitchell T, Knight J, et al. Contribution of dietary oxalate and oxalate precursors to urinary oxalate excretion. Nutrients. 2020;13:62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [52].Alshaikh AE, Hassan HA. Gut-kidney axis in oxalate homeostasis. Curr Opin Nephrol Hypertens. 2021;30:264–74. [DOI] [PubMed] [Google Scholar]
  • [53].Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nat Rev Genet. 2012;13:260–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [54].Chinda D, Takada T, Mikami T, et al. Spatial distribution of live gut microbiota and bile acid metabolism in various parts of human large intestine. Sci Rep. 2022;12:3593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [55].Vigsnaes LK, Ghyselinck J, Van den Abbeele P, et al. 2’FL and LNnT Exert antipathogenic effects against C. difficile ATCC 9689 in vitro, coinciding with increased levels of bifidobacteriaceae and/or secondary bile acids. Pathogens. 2021;10:927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [56].Koh A, De Vadder F, Kovatcheva-Datchary P, Backhed F. From dietary fiber to host physiology: short-chain Fatty acids as key bacterial metabolites. Cell. 2016;165:1332–45. [DOI] [PubMed] [Google Scholar]
  • [57].Ridlon JM, Ikegawa S, Alves JM, et al. Clostridium scindens: a human gut microbe with a high potential to convert glucocorticoids into androgens. J Lipid Res. 2013;54:2437–49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [58].Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761–72. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

medi-104-e43062-s001.pdf (1.4MB, pdf)

Articles from Medicine are provided here courtesy of Wolters Kluwer Health

RESOURCES