Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, clinically encompassing conditions such as Crohn's disease (CD) and ulcerative colitis (UC) (Bruner et al., 2023). IBD represents a globally prevalent chronic condition significantly impacting patients' quality of life. Epidemiological data indicate a rapid increase in incidence rates in emerging nations with historically low prevalence, while rates remain stable or are rapidly rising in Western countries (Kaplan and Windsor, 2021). The pathogenesis of IBD is thought to involve inappropriate and sustained inflammatory responses to commensal microorganisms in genetically predisposed individuals, although the precise mechanisms remain unclear (Khor et al., 2011).

Helicobacter pylori (H. pylori) infection is highly prevalent, affecting ~60% of the global population (Hooi et al., 2017). H. pylori is a major risk factor for the development of gastric cancer, and recent research has increasingly implicated H. pylori in the pathogenesis of other diseases. Cytotoxin-associated antigen A (CagA) and vacuolar cytotoxin A (VacA) are among the important virulence factors associated with H. pylori (Nejati et al., 2018).

Current evidence suggested that H. pylori infection may induce exacerbation of inflammatory responses, potentially contributing to the pathogenesis of IBD. However, some argued that H. pylori infection may have a protective effect against IBD. This controversial topic has led scholars worldwide to conduct numerous clinical studies, yet the clinical data remain contradictory, lacking consensus (Papamichael et al., 2014). Mendelian randomization (MR), which uses genetic variations to investigate causal relationships between exposures and outcomes, has emerged as a powerful tool to address the limitations and confounding factors present in observational studies (Emdin et al., 2017; Cai et al., 2023). This study applied MR analysis to elucidate causal relationships and guide further research into the pathogenesis of IBD.

In this study, we found an association between H. pylori infection and an increased risk of IBD, primarily linked to the risk of UC. Currently, the association between H. pylori infection and the risk of IBD diseases has been extensively studied, with some indicating that H. pylori infection may induce exacerbation of inflammatory responses, potentially being related to the pathogenesis of IBD.

Due to its microaerobic metabolism, helical shape, and unique motility, H. pylori easily colonizes the surface of the gastrointestinal tract (Sonnenberg, 2013). In inflammatory bowel disease, dysregulation of the host's immune response to commensal bacteria is considered a significant potential pathogenic mechanism. When the gastric mucosa mounts an immune response to H. pylori, products of the local immune reaction may disseminate to extragastric sites. In animal models, enterohepatic Helicobacter species such as H. hepaticus and H. bilis have been shown to induce sustained inflammation in the colon and cecum of immunodeficient rodents (Kullberg et al., 1998; Shomer et al., 1997). Some studies also suggested that infection may exert a protective effect on IBD by altering the diversity of the intestinal microbiota, subsequently modifying the local chemical characteristics of the intestine and the pattern of intestinal immune response (Feilstrecker Balani et al., 2023).

Regarding this controversial topic, scholars from various countries have conducted numerous clinical studies, yet their clinical data remain contradictory, lacking unified results. In a study involving 160 Chinese IBD patients (10%) and 80 control subjects (6.3%), there was no significant difference in the detection rate of Helicobacter genus in intestinal biopsy specimens (Zhang et al., 2011). Some studies had found a lower prevalence of H. pylori infection in IBD patients compared to control groups, suggesting a protective effect of H. pylori infection on the development of IBD (Jin et al., 2013). However, In one study, the PCR positivity rate for Helicobacter genus in UC patients was significantly higher compared to the control group (Thomson et al., 2011). Another study found that the H. pylori genus in the intestinal mucosa of CD patients was significantly higher than that in patients without inflammatory bowel disease through PCR (Oliveira et al., 2006). Clinical studies on H. pylori infection are inherently observational and lack randomization, prospective design, and blinding, leading to significant limitations and confounding factors such as differences in patient medication history and detection methods. Given this contradictory phenomenon, our study aimed to elucidate the potential causal relationship between H. pylori and IBD, the results of MR showed a causal relationship between H. pylori infection and increased risk of UC, but no causal relationship with CD. It is worth mentioning that, given the genetic IV sources of H. pylori infections included in this MR study, H. pylori infections here include both current and past infections. However, the current clinical trials have mainly focused on current H. pylori infections, which may also be the reason for the differences in results.

This study further explored the pathogenic virulence factors and identified an association between CagA and an increased risk of IBD, while VacA was not found to have a related effect. However, after FDR correction, there was no causal relationship between CagA and IBD (P = 0.0629) or between CagA and UC (P = 0.0587). Therefore, the correlation between H. pylori infection and increased risk of IBD may not be related to virulence factors. At the same time, two antibodies related to virulence factors, H. pylori VacA antibody and H. pylori CagA antibody, also represent some current H. pylori infections.

To assess the reliability of our study results, we conducted a series of sensitivity analyses. Cochran's Q-test, MR Egger, and leave-one-out analyses were employed, yielding robust results. These findings suggest that patients with H. pylori infection and associated intestinal symptoms may require screening for IBD. Furthermore, they provide insights for further exploration into the pathogenesis of UC. Perhaps further clinical or laboratory studies are needed to compare current H. pylori infections with previous infections. Further research is needed on the pathogenic factors involved. Meanwhile, it once again indicates the possible differences in the pathogenesis between UC and CD.

Although UC and CD have historically been studied together because they share common features, it is clear that they represent two distinct pathophysiological entities (de Souza and Fiocchi, 2016). Widespread activation of humoral immune response was observed in both diseases, resulting in various changes in immunoglobulin subclasses (MacDermott et al., 1989; Scott et al., 1986). A reported human epithelial colon self antigen recognized by tissue bound IgG antibodies in UC has not been recognized by CD mucosa (Takahashi and Das, 1985). This self antigen also exists in typical sites of extraintestinal manifestations of UC, suggesting that antibody mediated immune responses may be related to the intestinal and extraintestinal pathology of UC patients (Halstensen et al., 1993).

In addition, we found that a Mendelian randomization study on the same topic was published in February of this year (Yang et al., 2024), drawing a conclusion of no causal relationship. After comparing with the content of this article, the main reason for the different conclusions drawn is the different sources of H. pylori infection exposure data. Our genetic IVs were derived from a study in JAMA that identified genetic loci associated with susceptibility to H. pylori (Mayerle et al., 2013). Its diagnosis comes from serum anti Helicobacter pylori IgG and H. pylori antigen in feces, including current and previous infections. The final determined SNPs have P-values < 5 × 10⁻⁸. The H. pylori related genetic IVs obtained by Yang et al. were sourced from the EBI database, which includes Anti-H. pylori IgG Phenotype data from previous infections. There were no SNPs in this database with P-values < 5 × 10⁻⁸. When the conditions were relaxed to P-values < 5 × 10⁻⁶, 11 SNPs were selected for analysis. Therefore, this may not conflict with our research findings.

The current clinical research mainly focused on grouping analysis based on whether H. pylori is currently infected, and inconsistent results have been obtained from each group. In this MR analysis, after FDR correction, it was found that there is no causal relationship between virulence factor related IVs and IBD in some current infections, while genetic IVs determined based on current and past H. pylori infections have a causal relationship with IBD, especially UC. Currently, some studies had reported a suspected increase in the probability of IBD after H. pylori sterilization (Homolak et al., 2021; Chiba et al., 2016). A retrospective cohort study evaluated more than 5 million patients receiving H. pylori eradication treatment, and found that the incidence of IBD increased, and the incidence rate of UC in patients ≥ 30 years old increased more significantly (Mizukami et al., 2023). Therefore, based on current clinical reports and MR results, we speculate that a history of H. pylori infection is associated with an increased risk of IBD (especially UC). The reason for the increase in the incidence rate of IBD after H. pylori eradication may include factors of past H. pylori infection (antibody mediated immune response, changes in flora, etc.) in addition to antibiotics. However, this speculation cannot be validated through MR analysis and may require further clinical or laboratory research.

Our study suggests a potential causal relationship between H. pylori infection and IBD, especially UC. The effect may be more pronounced in individuals with previous H. pylori infections. Further research is needed on the pathogenesis of IBD.