To the best of our understanding, this study represents one of the initial attempts to comprehensively assess the causal associations between the GM and VTE, focusing on a genetic standpoint. In addition, employing the two-sample MR design, our investigation provides compelling evidence that the predicted abundance of certain gut microbial taxa, as determined by genetic factors, significantly contributes to the development and progression of VTE. By utilizing molecular genetic markers as IVs, the MR approaches effectively mitigate the influence of confounding factors such as socioeconomic status and cultural influences, as well as address issues of reverse causality(26). Family Porphyromonadaceae.id.943, phylum Cyanobacteria.id.1500, genus Eubacteriumrectalegroup.id.14374, genus LachnospiraceaeUCG001.id.11321, genus Coprococcus2.id.11302, family Christensenellaceae.id.1866, family Streptococcaceae.id.1850, and family Victivallaceae.id.2255 have been identified as playing causal roles in promoting the initiation of VTE. Conversely, family Oxalobacteraceae.id.2966, family Ruminococcaceae.id.2050, genus Erysipelatoclostridium.id.11381, genus Slackia.id.825, genus Actinomyces.id.423, and genus Anaerotruncus.id.2054 have been found to causally reduce the risk of VTE. The complete understanding of the involvement of the GM in the development of thromboembolism remains incomplete. However, our MR study has addressed this knowledge gap by investigating the potential contribution of the GM to VTE. Moreover, our study has explored the specific taxa that may either promote or hinder the initiation of VTE, providing a fresh perspective on this matter.
The recognition of the gut microbial involvement in diverse facets of human health is steadily growing. It assumes a pivotal function in multiple inflammatory conditions, and its manipulation presents a potential therapeutic avenue for such ailments. Several observational studies have documented the correlation between GM and VTE(27, 28). The activation of inflammatory pathways in vascular endothelial cells, platelets, and innate immune cells can be induced by perturbations of the gut microbiome caused by environmental or genetic factors(29). This activation subsequently leads to the release of various coagulation proteins, ultimately resulting in a prothrombotic state. The development of thrombosis is a multifaceted process involving intricate interactions among the coagulation system, innate immune system, and inflammation(30–32). Furthermore, inflammation is closely associated with dysbiosis, an increase in intestinal permeability, and the production of specific metabolites(33).
Porphyromonadaceae have been associated with cognitive dysfunction and the advancement of diabetes, as well as negative cardiac phenotype and obesity, as evidenced by previous studies conducted on both humans and animals(34–37). While primarily originating in the oral cavity, Porphyromonadaceae have also been linked to gut-related implications that extend beyond the local oral environment(38). Due to the metabolic activities of gut bacteria, particularly in relation to aromatic amino acids like tyrosine and phenylalanine, Porphyromonadaceae have the potential to produce phenolic compounds, with p-Cresyl sulfate (pCS) being one of its constituents(39). pCS is a prototype protein-bound uremic toxin that has been associated with numerous biological and biochemical (toxic) effects, including uremic cardiovascular disease (CVD)(40). Previous studies have shown a higher prevalence of Cyanobacteria, a phylum of bacteria, in individuals with CVD (41), as well as in mouse models of progeria(42). In the present study, an increased prevalence of family Porphyromonadaceae.id.943 and phylum Cyanobacteria.id.1500 is indicative of an elevated susceptibility to VTE. These findings propose that the identification of these specific bacterial strains in fecal samples may serve as a prognostic biomarker and a potential focus for effective intervention strategies in VTE.
Furthermore, we have identified three gut microbial taxa (Eubacteriumrectalegroup.id.14374, LachnospiraceaeUCG001.id.11321, Coprococcus2.id.11302) that have been found to have a positive causal relationship with DVT, in addition to the aforementioned two taxa that promote VTE. It is worth noting that Eubacteriumrectale is among the most prevalent bacterial species detected in human fecal samples(43). Previous MR analyses have provided support for a potential causal effect of Eubacteriumrectale in reducing plasma levels of hydrogen sulfite, a toxin known to impact cardiovascular function(44). Additionally, the reduction in Eubacteriumrectale has been found to be associated with cerebrovascular events in patients with refractory hypertension(45). LachnospiraceaeUCG001 has been identified as being involved in the synthesis of glutamate, butyrate, serotonin, and gamma amino butyric acid (GABA), which are crucial neurotransmitters associated with depression(46). Additionally, this microbial species may potentially contribute to the health of adults at risk for cardiovascular conditions(47). Notably, studies have suggested that Coprococcus2, as part of the intestinal microbiome, may influence age-related phenotypes, such as weight loss(48). This study has provided initial evidence of a potential causal association between the three taxa and the risk of DVT. However, further research is warranted to elucidate the underlying biological mechanisms linking these taxa to DVT. Additionally, our investigation has identified Oxalobacteraceae.id.2966, Ruminococcaceae.id.2050, Erysipelatoclostridium.id.11381, and Slackia.id.825 as being associated with the suppression of DVT. A previous study has indicated the presence of distinct members of the Oxalobacteraceae family in human atherosclerotic plaques derived from common carotid arteries of individuals with atherosclerosis, albeit at relatively low abundances within the total population of the 16S rRNA gene(49). Furthermore Ruminococcaceae, Ruminococcaceae UCG-002 and Ruminococcaceae UCG-003 have been identified as the primary contributors to the observed positive correlation between chronic insomnia and CVD(50). Atherosclerosis serves as the primary etiology of CVD, with hypercholesterolemia and hyperlipidemia acting as the principal risk factors for atherosclerosis development. The mitigation of hypercholesterolemia can be achieved through the reduction of Erysipelatoclostridium abundance and the activation of butanoate and vitamin B6 metabolism(51). In heart failure patients without sarcopenia, Slackia was found to be significantly enriched. Consequently, targeting this taxon may present a novel approach for preventing and treating sarcopenia in heart failure patients(52). The present study provides evidence supporting a reasonable correlation between specific gut microbiota taxa, as identified in our MR study, and the occurrence of DVT. The present study provides evidence supporting a reasonable correlation between specific gut microbiota taxa, as identified in our MR study, and the occurrence of DVT.
It is important to note that VTE, encompassing PE, is a prevalent condition associated with substantial morbidity and mortality. Our findings indicate that certain gut microbiota, such as Christensenellaceae.id.1866, Streptococcaceae.id.1850, and Victivallaceae.id.2255 are linked to the development of PE. Christensenellaceae, a producer of short-chain fatty acids, exhibited a noteworthy decrease in fecal samples obtained from Ldlr-/-( Casp1-/-) mice, potentially impacting the progression of atherosclerosis(53). In addition, Christensenellaceae_R-7 was observed to be significantly more abundant in the normotensive group compared to the hypertensive group(54). Numerous studies conducted on hypertensive individuals similarly revealed a loss and reduced abundance of bacteria capable of producing butyrate following the onset of obesity. In contrast, the augmentation in the abundance of certain streptococcus taxa may be attributed to variances in BMI and waist circumference(55). Furthermore, a prior MR analysis demonstrated an association between Victivallaceae and an increased risk of chronic obstructive pulmonary disease(56). Furthermore, we identify two gut microbiota taxa (Actinomyces.id.423, Anaerotruncus.id.2054) that exhibit a negative causal relationship with PE, which is a novel finding. Nitric oxide (NO), a small gaseous and multifunctional signaling molecule, plays a crucial role in maintaining metabolic and cardiovascular homeostasis. Actinomyces, being the most abundant among nitrate-reducing bacteria, has been linked to endothelial dysfunction and cardiovascular risk(57). The administration of chenpi extract resulted in an increase in both the abundance and diversity of fecal microbiota. Additionally, the abundance of Anaerotruncus was significantly elevated following chenpi extract treatment, and this increase showed a significant negative correlation with serum lipid parameters(58). In conjunction with the previously obtained findings, our MR study posits the potential for mitigating and managing PE through the augmentation of negatively influential gut microbiota taxa via diverse approaches. The collective evidence from our MR study substantiates a plausible association between the GM and PE.
Given the direct interconnection of gastrointestinal tracts and the established impact of GM on the progression of systemic diseases, a comprehensive understanding of the precise role played by distinct gut microbe taxa in VTE could offer novel prospects for enhanced preventive and management strategies. Despite previous endeavors to elucidate the correlation between VTE and GM, no conclusive evidence has been put forth to establish a causal relationship. Moreover, despite the identification of dysbiosis of the GM as a phenotype in patients with VTE, it is important to note that this dysbiosis is a result of a complex combination of multiple factors, and the specific changes in diverse taxa of microbiota are not consistent. Additionally, the composition of the GM may vary due to inconsistencies in the staging of VTE. As previously mentioned, MR is an ideal study design for investigating the causal relationship between potential risk factors and diseases of interest. In recent times, numerous MR studies have been conducted to elucidate the impact of modest risk factors on VTE. By conducting studies on the factors that influence the risk of VTE, MR research aids in the development of public health policies and clinical interventions that efficiently decrease the occurrence and societal impact of VTE.
This study represents a pioneering effort in the field of MR research, as it utilizes extensive data on the GM and genetic factors related to VTE to investigate the potential causal relationship between GM and the risk of VTE. The current MR analysis offers several notable advantages. Firstly, our study effectively addresses the issue of causality and confounding variables through the robust implementation of the MR method. Secondly, our MR study encompasses a broad population sample at a relatively low cost, thereby enhancing the practicality and persuasiveness of our findings compared to traditional observational studies. Thirdly, this study presents the first evidence of a causal relationship between GM and VTE from a genetic standpoint. Additionally, the F-statistic of the instrumental variables (IVs) employed in our analysis all exceeded the threshold of > 10, indicating a reduced likelihood of weak instrument bias. Future research in the field will focus on investigating causal associations to better understand the role of GM in disease development. The findings of our MR analysis can serve as a valuable resource for selecting specific gut bacteria for further investigation into the pathogenesis of VTE.
Nevertheless, it is important to acknowledge the limitations of this study. Firstly, the analysis of bacterial taxa was limited to the genus level, without further exploration at more specific levels such as species or strain. Secondly, it is worth noting that most participants in this GWAS were of European descent, potentially impacting the generalizability of the findings. Therefore, caution should be exercised when applying the results of this study to populations of different ethnic backgrounds. Thirdly, in order to ensure an adequate number of instrumental variables (IVs), we employed a significance threshold of p < 1.0×10− 5 for the selection of GM IVs, surpassing the conventional genome-wide significance level of p < 5×10–8. Moreover, it is important to note that the impact of the bacterial traits we observed was relatively modest, and there were no other independent GWAS investigating VTE with a sufficiently large sample size to corroborate our findings. Fourthly, our study specifically aimed to elucidate the risk factors for VTE in order to facilitate comprehensive clinical intervention and mitigate the incidence of this condition. Consequently, we focused on examining the unidirectional influence of 196 gut microbial taxa on VTE. Fifthly, this study has not fully explored the precise mechanisms through which the aforementioned gut microbial taxa impact the risk of VTE. Additionally, despite the identification of numerous VTE cases in the present GWAS analysis, stratification or adjustment for these cases was not feasible. Naturally, larger sample sizes in clinical studies and experiments are necessary to validate our findings. Lastly, given the unavailability of information regarding VTE subtypes, further investigations are warranted once this information becomes accessible.