Use of Mendelian Randomization to Unveil Metabolic Markers in Helicobacter pylori Infection

Enzymes encoded by Helicobacter pylori are involved in various metabolic processes. Using a Mendelian randomization (MR) framework, we investigated the metabolites associated with six antibodies against H. pylori and explored the potential underlying biological pathways.

A meta-analysis of 65 genome-wide association studies was conducted to assess the genetic predisposition to approximately 3,550 metabolites. Summary-level data for > 10 million genetic variants associated with H. pylori antibodies were extracted from the UK Biobank. MR analysis was performed using inverse-variance weighting, weighted median, and Egger regression to ensure robust findings. Significant metabolites were further analyzed using enrichment analysis to identify the relevant biological pathways.

A total of 100 metabolites were positively associated with H. pylori antibodies (cytotoxin-associated gene A [CagA], 16; catalase, 25; GroEL, 16; outer membrane protein [OMP], 22; urease [UREA], 15; and vacuolating cytotoxin [VacA], 6). These metabolites were linked to pathways involving the metabolism of alanine, aspartate, glutamate, glycine, serine, threonine, purine, and tryptophan in four antibodies. Additionally, 67 metabolites were negatively associated with H. pylori antibodies (CagA, 11; catalase, 6; GroEL, 13; OMP, 11; UREA, 11; and VacA, 15). These metabolites were primarily involved in pyrimidine metabolism in the three antibodies.

Our study identified numerous metabolites linked to H. pylori antibody levels, indicating that metabolic alterations are associated with infection. These changes were particularly enriched in pathways involved in amino acid, nucleotide, and coenzyme metabolism and biosynthesis. These findings highlight the systemic metabolic impact of H. pylori infection and offer insights into the biological mechanisms underlying host-pathogen interactions.