Our MR analysis has revealed a nuanced tapestry of metabolites associated with VMS, shedding light on potential protective and contributory roles in this complex phenomenon. The intricate interplay between these metabolites not only provides insights into the molecular landscape of VMS but also prompts a deeper exploration of their physiological significance.
Among the protective metabolites, Mannose, a sugar found in fruits and vegetables[22], and Isoleucine, an essential amino acid abundant in meat, poultry, fish, and eggs, stand out[23]. These findings resonate with the broader literature on nutrition, where the protective effects of certain dietary components against VMS have been suggested. Mannose, once converted to glucose, serves as an energy source, while Isoleucine contributes to muscle tissue building and repair[23]. Leveraging these metabolic pathways through dietary interventions could offer novel avenues for therapeutic exploration, aligning with the growing emphasis on personalized nutrition in managing menopausal symptoms.
It was reported that stearic acid, like oleic acid, may have a distinct role in influencing postprandial lipid responses, suggesting potential protective effects for mildly hypercholesterolemic postmenopausal women[24]. Similarly, the negative associations of Stearate and Ascorbate on VMS were also estimated and enriched in lipid metabolism and essential functions like immune response and collagen production. This is consistent with what was reported that stearic acid, like oleic acid, may have a distinct role in influencing postprandial lipid responses, suggesting potential protective effects via regulation of fecal bile acid metabolism for mildly hypercholesterolemic postmenopausal women[24]. The 10-undecenoate, which could be increased in serum with habitual consumption of butter and alcohol, was reported to impact lipid metabolism[25]. And the energy-related functions of 3-dehydrocarnitine add further dimensions to the potential mechanisms through which these metabolites may influence VMS. These findings also inspired researchers for developing targeted interventions for relieving VMS especially in the respective of nutrition. The inverse association observed with 4-androsten-3beta,17beta-diol disulfate 1, a steroid hormone, introduces a complex layer to our understanding. While not directly sourced from food, it is influenced by genetic variants in the gene SULT2A1 which was reported to be involved in the sulfation of steroid hormones, including estrogen, which contributes to the inactivation of these hormones[26]. Further research is warranted to elucidate the specific role of this hormone and its potential modulation for perimenopause symptom management.
Conversely, metabolites such as Inosine, Myristate, Gamma-glutamylleucine, Glucose, and Serine displayed positive associations with VMS. These metabolites served as risk factors for VMS indicating potentially linking disruptions in energy metabolism, lipid biosynthesis, and response to hormonal stimuli to the manifestation of symptoms. Inosine, derived from purine-containing foods like meat, fish, and eggs, may indicate increased purine breakdown[27], potentially linking higher dietary intake to an elevated risk of VMS. Inosine has been studied for its potential modulatory effects on adenosine receptors which play essential roles in regulating coronary microcirculation specially maintaining adequate blood flow to meet the demands of the myocardium[28]. Elevated Myristate levels associated with saturated fats could contribute to VMS severity, reflecting the impact of dietary fats on hormonal balance. Increased Gamma-glutamylleucine levels, a derivative of leucine, may signify disruptions in protein metabolism with implications for metabolic pathways associated with VMS. Elevated glucose levels resulting from a high-fat, high-sugar diet may indicate disturbances in carbohydrate metabolism, influencing VMS severity. While Serine itself may not be directly impacted, variations in amino acid balance influenced by overall dietary context and protein intake may contribute to the intricate interplay between nutrition and hormonal regulation influencing VMS. These findings also emphasize the need to consider dietary patterns, especially those rich in fats and sugars, in understanding the complex relationship between diet, metabolites, and VMS during perimenopause.
Compare Mannose and Glucose to illustrate how high-sugar intake of different compound would lead to different outcome. the contrasting roles of mannose as an immune modulator with anti-inflammatory properties[29] and glucose as a promoter of inflammation underscore the intricate relationship between sugar metabolism and immune responses. While mannose shows promise in immune regulation[29], the impact of glucose on inflammation emphasizes the importance of maintaining balanced glucose levels for overall health and the prevention of chronic inflammatory conditions. Not as abundant in the diet as other sugars like glucose and fructose, mannose is contained in fruits like blueberries, cranberries and vegetables like green beans and cabbage. And capsicum and aloe vera are source of mannose and have relatively low level of glucose and fructose.
Myristate, stearate, and 10-undecenoate, all exhibiting protective effects against vasomotor symptoms (VMS), are fatty acids with distinct metabolic properties. Myristate, classified as a saturated fatty acid, is found in red meat, coconut oil, and dairy products. The protective effect of myristate may be linked to its impact on lipid metabolism, contributing to a hormonal balance that alleviates VMS. Similarly, stearate, another saturated fatty acid present in beef and certain butter could influence lipid and lipoprotein concentrations, promoting a favorable lipid profile and indirectly contributing to VMS regulation. 10-undecenoate, identified as an unsaturated fatty acid and increased with the consumption of butter and alcohol, suggests a connection to lipid metabolism. Understanding these fatty acids' metabolic roles, particularly in hormonal pathways, provides insights for potential dietary interventions to alleviate menopausal symptoms.
Isoleucine and Serine play contrasting roles in the context of vasomotor symptoms (VMS) during perimenopause. Isoleucine, an essential amino acid abundant in certain foods, appears to be a protective factor against VMS. Its influence extends beyond basic nutrition, impacting neurotransmitter regulation and neural processes. This suggests that Isoleucine may play a crucial role in maintaining hormonal balance, potentially mitigating the severity of VMS. Conversely, Serine is identified as a risk factor for VMS. While not directly implicated, variations in amino acid balance influenced by overall dietary context and protein intake could contribute to the complex interplay between nutrition and hormonal regulation affecting VMS. The distinct roles of Isoleucine and Serine emphasize the significance of individual dietary components in influencing the hormonal and neural mechanisms associated with VMS.
The PPI network offers a structural framework, emphasizing the need for targeted investigations into specific biological processes and their contributions to VMS. For the 10 hub genes, MME, encoding membrane metalloendopeptidase, is implicated in neuropeptide metabolism, potentially influencing neuroendocrine pathways related to VMS[30]. CCND1, a cell cycle regulator, suggests a role for cell cycle dynamics in VMS etiology. TNF, known for its proinflammatory role, aligns with the growing understanding of inflammation in VMS manifestation[31]. ITGB1, involved in cellular adhesion, hints at the importance of tissue integrity. PTGS2, encoding a key enzyme in prostaglandin synthesis, connects with hormonal pathways. HSP90AA1, a heat shock protein, may signify cellular stress responses in VMS. CTSB, a lysosomal enzyme, suggests involvement in cellular degradation processes. PPARG and PPARA, members of the peroxisome proliferator-activated receptor family, point towards potential regulatory roles in metabolic pathways linked to VMS[32]. CXCL8, a chemokine, implies immune system modulation. The collective implications of these hub genes underscore the intricate interplay between hormonal, inflammatory, and metabolic processes in the manifestation of VMS.
Furthermore, the enrichment results provide additional context to these associations. The top-enriched biological function, neuroactive ligand-receptor interaction, implies a comprehensive impact on neural signaling, aligning with the observed protective roles of certain metabolites. Response to hormone enrichment indicates broader hormonal influences, reinforcing the notion that hormone dysregulation extends beyond the classic menopausal hormonal changes. Metabolism of lipids, another highly enriched function, sheds light on the interconnectedness of lipid-related genes with VMS. Disruptions in lipid metabolism, implicated in cardiovascular and metabolic disorders, may contribute to the multifaceted nature of menopausal symptoms. The responses to xenobiotic stimulus and behavior enrichments further underscore the complexity of VMS, implicating potential connections to detoxification processes and behavioral aspects.
This detailed exploration of metabolite-gene-biological process-VMS associations not only broaden the scope beyond the HPA axis but also underscores the need for a holistic understanding of menopausal symptoms. Tailoring interventions to address this complexity, considering multiple biological processes, is crucial for developing effective strategies to manage VMS and related health challenges. Further research into the specific mechanisms linking these metabolites, genes, and biological processes will be essential for advancing our understanding and therapeutic approaches.
While our study offers valuable insights into the potential causal associations between metabolites and VMS, several limitations should be considered. Firstly, the MR analysis relies on specific assumptions, including the relevance, independence, and exclusion restriction assumptions. While we have taken measures to address these assumptions rigorously, inherent limitations associated with MR analyses persist. Furthermore, our study utilized data primarily derived from a metabolite genome-wide association study, which included genetic association evidence for 486 metabolites. This dataset might not encompass the entirety of metabolites potentially associated with VMS, and the specific metabolites examined may not fully represent the complexity of the metabolic landscape linked to VMS. And the association between lipids and VMS were to be analyzed in further research. Moreover, As the VMS genome-wide summary statistics were obtained from a case-control study, although this dataset provides substantial statistical power, it is crucial to acknowledge the inherent heterogeneity within the population. Variability in VMS presentation, severity, and underlying etiological factors among individuals may not be fully captured by the available data. In our exploration of the genetic basis of VMS, we utilized public available GWAS dataset from a population-based cohort. While this approach offers a large sample size, it introduces potential biases associated with data collection methods and the reliance on health records, which may not comprehensively capture the complexity and nuances of VMS. Additionally, the study predominantly focused on European cohorts, limiting the generalizability of our findings to populations of different ancestries. The genetic instruments used in the MR analysis may not fully encompass the genetic diversity present in individuals of non-European ancestry. Future research endeavors should prioritize the inclusion of more diverse cohorts to ensure the broader applicability of findings and enhance our understanding of the causal associations between metabolites and VMS across different populations.