The present study investigated the causal relationship of 179 lipid species with syphilis using two-sample and multivariate MR analyses. Our findings indicate that several SEs, specifically SE (27:1/16:0), SE (27:1/18:2), SE (27:1/18:3), SE (27:1/20:3), and SE (27:1/22:6), were linked to an increased risk of syphilis in univariate MR analyses. Additionally, PC (18:2_0:0) was also related to an elevated risk of syphilis, while PC (16:1_18:0) appeared to have a protective effect. However, in multivariate MR analyses, only PC (16:1_18:0) remained significantly associated with syphilis, suggesting a more complex interplay between lipid species and syphilis risk.

Lipids are complex molecules that cells produce from simple components through enzymatic mechanisms (Wang et al. 2020). The biological role of lipids is determined by the structure of their head group. Each class of lipids encompasses a multitude of distinct molecular species that possess identical head groups but vary in the length of their acyl chains, the count of double bonds, and the characteristics of their chemical bonds (Zahednezhad et al. 2019). This class of lipids is a common feature across all cell types and the frequently studied model organisms, which include mammals, fruit flies, roundworms, and yeast (Kimura et al. 2016). The ubiquity of these lipid classes across different species suggests that they have been evolutionarily conserved (Han and Gross 2022). However, it’s important to note that the specific types of lipid molecules can vary among different organisms. Lipids are known to have a significant impact on the pathophysiological processes of infectious diseases. Research has demonstrated that lipids have the capacity to alter the progression of various infections, including tuberculosis, human immunodeficiency virus (HIV), and malaria (Haughey et al. 2011; Kim and Shin 2023; Wagner and Chitnis 2023). The study showed that syphilis infection may cause lipid metabolism disorders (Xiao et al. 2019). Lipids can affect the integrity of cell membranes, influence immune responses, and serve as signaling molecules. Certain lipids might facilitate the entry and replication of pathogens, while others may have protective roles (Rameshwaram et al. 2018). Our results align with these findings, demonstrating that specific lipid species, such as SEs and PCs, can influence syphilis risk. The association of SEs with increased syphilis risk may be due to their role in modulating membrane fluidity and permeability, thus affecting the susceptibility to infection. SEs regulate immune cell function, such as altering the activity and function of T cells, B cells and macrophages, affecting immune response(Choi et al. 2017). As a component of cell membrane, it can affect membrane fluidity and permeability, change the distribution and activity of receptors on the surface of immune cells, and affect the processes of antigen recognition, signal transmission and immune molecule secretion of immune cells(Skornick et al. 1984). In addition, SEs can also regulate the activity of key molecules in inflammatory signaling pathways, such as inhibiting the activation of inflammatory transcription factors such as NF-κB, thus affecting the intensity and process of immune response(Jarc and Petan 2020). Conversely, the protective effect of PC (16:1_18:0) might be attributed to its role in maintaining membrane stability and modulating immune responses. PCs, as a cellular immune enhancer, can effectively promote the proliferation and activation of T lymphocytes and play the function of immune regulation(Shahine et al. 2019). In addition, it is also an important part of cell membranes, essential for maintaining the normal structure and function of immune cells, and changes in its content and composition will affect the activity, proliferation and differentiation of immune cells. PCs has anti-inflammatory properties, which can regulate the function of inflammatory cells, inhibit the chemotaxis, activation and release of inflammatory mediators of inflammatory cells(Eros et al. 2009; Treede et al. 2007). It can also affect the transduction of inflammatory signals by regulating the fluidity and stability of cell membranes, thereby reducing inflammatory responses.

Many lipids lost meaning in MVMR, suggesting that their associations observed in univariate analyses may be confounded by other lipids. This highlights that these associations may not represent true causation. Non-significant associations in MVMR do not confirm the absence of an effect, but rather indicate the complexity of lipid metabolism and its interaction with syphilis risk. The single important finding of our analysis - the protective effect of PC (16:1_18:0) against syphilis - provides an important signal that warrants further investigation. Future studies should consider larger sample sizes and diverse populations to further dissect these relationships.

The significance of our findings lies in the potential for targeted therapeutic interventions and risk assessment in syphilis. Identifying specific lipid species that influence syphilis risk provides a foundation for developing lipid-modulating treatments that could potentially mitigate infection risk. Further research, especially studies that involve larger sample sizes and a more diverse range of populations, is essential to validate these observed associations and to uncover the fundamental mechanisms at play. By delving into the interplay between lipid metabolism and the immune system’s reaction to Treponema pallidum, which is the bacterium responsible for causing syphilis, we may gain a more profound understanding of the disease’s pathogenesis. This could potentially lead to the development of new therapeutic strategies or preventive measures against syphilis.

Our study has several limitations. First, the observational nature of MR studies cannot entirely rule out residual confounding. Second, our analyses were based on genetic variants associated with lipid levels, which may not capture the entire spectrum of lipid metabolism. Third, the study population primarily was predominantly composed of individuals with European ancestry, which might restrict the applicability of our results to other ethnic groups. Additionally, the complexity of lipid interactions and their dynamic changes during infection were not fully accounted for in our analysis.

In conclusion, our study highlighted the significant associations between specific lipid species and syphilis risk. The protective role of PC (16:1_18:0) and the risk-enhancing effect of certain SEs provided new insights into the lipid-mediated mechanisms in syphilis. These results could have significant implications for clinical practice, particularly in the realm of developing therapies that target lipid profiles and the creation of preventive strategies focused on lipid management. Further research is warranted to explore the mechanistic pathways linking lipid species to syphilis and to validate our findings in diverse populations.