Multiple sclerosis (MS) is a common cause of adult disability, characterized by chronic inflammatory demyelination and neurodegeneration within the central nervous system [1]. MS typically manifests during the productive stages of individuals' lives, when they are planning families and establishing careers, thereby exerting a significant impact on affected individuals, their families, and society [2]. Global estimates indicate that MS currently affects 2.8 million adults worldwide [2]. The complex etiology and pathogenesis of MS result from the interplay of genetic and environmental factors. Factors such as Epstein-Barr virus, sunlight (UV exposure), smoking, vitamin D, along with individual genetic backgrounds, play crucial roles in the causal pathways leading to the onset of MS [3]. Identifying the risk factors for multiple sclerosis contributes to a better understanding of its pathogenesis and enables the provision of care and treatment strategies for patients and healthcare professionals.
Helicobacter pylori (H. pylori) is a Gram-negative bacterium that colonizes the human gastric mucosa, leading to gastritis in approximately half of the global population [4]. Currently, it is recognized that H. pylori infection is closely associated with gastritis, duodenal ulcers, gastric cancer, and other gastrointestinal issues [5]. H. pylori can also release various toxins and effector proteins, including cytotoxin-associated gene A (CagA), outer membrane vesicles (OMV), outer inflammatory protein A (OipA), vacuolating toxin gene A (VacA), heat shock protein A (HtrA), outer membrane protein (OMP), and neutrophil-activating protein A (NepA) [6]. Among these, CagA is a virulence factor associated with disease severity, capable of influencing multiple cellular processes. Additionally, VacA has diverse functions, ranging from inducing cell apoptosis to modulating the immune system [7]. Both of these factors impact cell morphology and immune cells, potentially leading to elevated levels of autoimmune antibodies [7].
The infectious agent induces autoimmunity through two distinct mechanisms. Initially, it elicits homologous antigen-specific signals via molecular mimicry or the mobilization of endogenous antigens. Simultaneously, it incites inflammation, generating antigen-specific signals that bolster the immune response through a phenomenon known as the adjuvant effect [8]. Presently, H. pylori infection has been linked to a range of autoimmune diseases, such as inflammatory bowel disease, autoimmune metabolic disorders, autoimmune liver diseases, systemic lupus erythematosus, and others [9]. However, there is significant controversy surrounding whether H. pylori infection, as one of the most common environmental factors associated with MS, is causally linked to the disease. Some studies indicate that H. pylori infection could worsen MS as a risk factor [10, 11], while others propose the opposite, suggesting that H. pylori infection might actually act as a protective factor, reducing the risk of developing MS [12–15]. Additionally, certain research suggests that there may be no direct causal relationship between H. pylori infection and MS [16, 17]。In recent years, conflicting conclusions have emerged from two meta-analyses. Delaram Arjmandi et al. posit that active H. pylori infection could be a risk factor for the development of MS [18], while Sangharsha Thapa et al. argue against a causal association between H. pylori infection and MS [19]. Therefore, exploring the causal relationship between H. pylori infection and multiple sclerosis remains a focal point of our research, as it impacts the treatment strategies for MS patients.
Currently, the causal relationship between H. pylori infection and multiple sclerosis is limited to observational studies, which have inherent limitations such as unmeasured or imprecisely measured confounders, reverse causation, and other sources of bias. To address these limitations, leveraging data from genome-wide association studies (GWAS) for Mendelian randomization (MR) has emerged as a promising approach for evaluating causal relationships in assumed exposure-outcome pathways [20]. Essentially, MR acts as a natural randomized trial, utilizing the random allocation of genetic variants at conception to partition individuals into different subgroups, akin to a placebo group and an intervention group in a randomized controlled trial. This method can assess potential causal relationships between risk factors (H. pylori infection) and disease outcomes (such as MS), while ensuring that confounding variables are also random [21]. In our study, we have curated the latest GWAS summaries on H. pylori infection and MS. Utilizing a two-sample MR analysis, our central objective is to elucidate the causal relationship between these factors. This pursuit is pivotal in unraveling the pathogenesis of MS and pinpointing prospective therapeutic targets.