AD progresses rapidly with severe consequences often arising from aortic rupture and organ ischemia, underscoring the importance of investigating its etiology and preventive strategies. Current research attributes the occurrence of AD primarily to intrinsic vascular pathology and hemodynamic factors. Structural alterations of the aortic wall serve as a crucial foundation for the development of AD30. However, the molecular mechanisms underlying degenerative changes in the aortic wall remain unclear, and effective measures for preventing the formation, progression, and rupture of AD are currently lacking. Some studies propose that inflammation and oxidative stress play pivotal roles in the process of AD formation. Levels of certain pro-inflammatory cytokines and chemokines, for instance, such as tumor necrosis factor (TNF)-α, Interferon(IFN)-γ, Interleukin(IL)-1, and IL-2, are significantly elevated in AD patients 31. Simultaneously, the accumulation of numerous inflammatory cells in the vessel wall can directly damage the aortic wall by secreting proteases that degrade the extracellular matrix (ECM) of the aorta. For instance, macrophages and neutrophils secrete MMP-9, elastase, and collagenase, which can directly degrade the ECM, potentially leading to detachment of smooth muscle cells (SMCs) from the ECM and cell death32. Lampson and colleagues' research also discovered that increased generation of endothelium-specific reactive oxygen species heightened susceptibility to AD, with the production of reactive oxygen species being closely linked to the inflammatory process33. Therefore, endeavoring to comprehend and research the pathogenesis of AD from the perspective of inflammation is both necessary and worthwhile.
As for the gut microbiota, a substantial body of recent research has confirmed its significant impact on inflammatory processes. Under healthy conditions, the functionality of the intestinal epithelial barrier is maintained through several mechanisms related to the balance of the gut microbiota, including the restoration of tight junction protein structures, upregulation of mucin genes, and inhibition of binding between epithelial cells and pathogenic bacteria34. However, when the gut microbiota becomes imbalanced, intestinal permeability increases, leading to the translocation of certain bacteria and their harmful metabolites from the gut into the circulation, thereby inducing an inflammatory response in the body. Hence, disruption of barrier function due to intestinal ecological imbalance stands as a pivotal factor in the initiation of the inflammatory process and related inflammatory diseases35,36. Similarly, we postulate that this process is likely to be involved in the pathogenesis of AD.TMAO, for example, is one of the significant metabolic products of gut microbiota37. Elevated TMAO levels can induce activation of the nuclear factor-κB (NF-κB) pathway and upregulation of pro-inflammatory gene expression, including genes encoding inflammatory cytokines, adhesion molecules, and chemokines, thereby promoting the occurrence of inflammation in the body38. Furthermore, through metabolomic analysis of serum from AD patients, a significant elevation in TMAO levels was observed in individuals with AD10. This finding prompts us to consider whether there is a more intricate connection between gut microbiota and the onset and progression of AD. This raises the question of whether gut microbiota has a more direct association with the occurrence and progression of AD. While the association between gut microbiota and cardiovascular diseases is gradually being recognized 39,40, it seems that little attention has been paid to the altered characteristics of gut microbiota in AD patients. The limited current research might be attributed to the critical nature of AD, where urgent surgery is often imperative. Additionally, the low incidence and high mortality rate of this disease pose challenges for researchers to gather a sufficient number of patient samples. Jiang et al. employed high-throughput 16S rDNA sequencing of fecal samples from AD patients and discovered differences in gut microbiota composition between AD patients and healthy individuals. Genera such as Prevotella, Porphyromonas, Lachnospiraceae, and Ruminococcus, as well as inflammation-associated genera Fenollaria and Sutterella, were found to be more enriched in the AD group16. Furthermore, Zheng et al. analyzed changes in the gut microbiota of 40 patients with thoracic aortic dissection before and after surgery and found increased levels of Oscillibacter, Anaerotruncus, Alistipes, and Clostridium difficile after surgery41. However, these aforementioned observational studies had small sample sizes and could not completely eliminate the interference of confounding factors. Therefore, performing large-sample Mendelian randomization (MR) analyses based on public databases becomes particularly important. Our MR analysis results provide evidence for a causal relationship between the Lachnospiraceae ND3007 group of the phylum Firmicutes and the onset of AD, and this association is positively correlated with the occurrence of AD. This is consistent with prior research by Jiang et al., who similarly found an enrichment of Lachnospiraceae in the AD group. Lachnospiraceae is a prominent group within the phylum Firmicutes, and numerous studies in animals and humans have confirmed that various bacteria within the Firmicutes phylum are major producers of TMAO42. This provides further evidence to support the hypothesis we mentioned earlier regarding the relationship between gut microbiota and AD. However, the role of Lachnospiraceae has been debated in previous research. Given that obesity is widely recognized as a precursor to cardiovascular diseases, a study focused on an Italian population confirmed its higher abundance in obese and overweight individuals43.On the other hand, Lachnospiraceae has been found to be negatively correlated with diseases such as depression and Alzheimer's disease44. Results of Mendelian randomization by Xiang et al. also suggest that Lachnospiraceae is a protective factor for systemic lupus erythematosus45.In terms of the immune response, individuals with a higher abundance of Lachnospiraceae in chronic urticaria show better responses to antihistamine treatment46. These findings suggest that gut microbiota such as Lachnospiraceae may exert their effects on various systems and organs within the human body through different pathways.
Currently, treatment options for AD are limited, and there is a lack of effective pharmacological treatments specifically for AD. Once AD occurs, surgical intervention, despite its potential for extensive damage and poor prognosis, remains the fundamental treatment approach. Therefore, effective prevention, early diagnosis, minimally invasive treatments, and recurrence prevention are currently key areas of research focus for AD. For instance, Guo et al. found that blocking IL-1β can reduce the evolution of thoracic aortic dissection in a rodent model and suggested that IL-1β might be a molecular target for future AD prognosis and drug therapy47. Therefore, exploring the pathogenesis of AD from the perspective of gut microbiota may contribute to identifying novel drug targets for new therapeutic approaches. Currently, the utility of probiotics in altering gut microbiota has become an important approach for preventing and treating cardiovascular diseases. In a clinical trial, it was found that combining prebiotic inulin and Lactobacillus rhamnosus in patients with coronary artery disease significantly reduced inflammatory biomarkers such as TNF-α and LPS48. Therefore, utilizing probiotics to regulate gut microbiota imbalance might be beneficial for the prevention of AD.
To the best of our knowledge, our study represents the first Mendelian randomization analysis of the relationship between gut microbiota and AD. Unlike previous observational studies, MR analysis, eliminating confounding factors such as hypertension, smoking, and atherosclerosis, provides the first genetic evidence of a causal relationship between gut microbiota and AD. This underscores the significant impact of genetically predicted specific gut microbiota abundance on the occurrence of AD, a factor that cannot be overlooked. Simultaneously, this offers new avenues for both the treatment and prevention of AD. However, our study has limitations. Firstly, we are unable to elucidate the direct mechanisms by which alterations in specific gut microbiota impact the occurrence of AD; our findings can only be combined with prior research results to formulate potential hypotheses. Secondly, the dataset employed in this study originates from a GWAS database of European populations, and the conclusions drawn may not be generalizable to other populations. Finally, our study cannot rule out the possibility of a nonlinear relationship between gut microbiota and the pathogenesis of AD.