Abstract
Background: Emerging observational and clinical studies have highlighted the role of gut microbiota in hematologic malignancies, including malignant lymphoma. However, conflicting findings persist regarding the causal direction of this relationship, as traditional studies are susceptible to confounding factors and reverse causality. Mendelian randomization (MR) analysis, leveraging genetic variants as instrumental variables (IVs), offers a robust approach to infer causality by minimizing these biases. Here, we investigate the bidirectional causal links between gut microbiota and malignant lymphoma, addressing controversies in existing population-based studies. Methods: Bidirectional two-sample MR analysis was used to examine the causal relationship between malignant lymphoma and gut microbiota. The summary-level data of gut microbiota was obtained from the MiBioGen Consortium, a large-scale genome-wide study, involving 18,340 participants from a multiethnic cohort. Summary statistics for malignant lymphoma were sourced from the OpenGWAS website, which contains data from 490,803 participants. Using the standard quality-controlled single-nucleotide polymorphism (SNP) as an IV, we examined the potential causative link between gut microbiota and malignant lymphoma via the inverse variance weighting, MR Egger, weighted median, weighted model, and simple mode. Reverse MR analysis was further conducted on bacterial taxa identified as causally associated with malignant lymphoma in the forward MR analysis. Results: Seven causal relationships between gut microbiota and malignant lymphoma were found, including the phylum Bacteroidetes [odds ratio (OR) =1.31; 95% confidence interval (CI): 1.02-1.68; P=0.03], the class Bacilli (OR =1.22; 95% CI: 1.00-1.49; P=0.048), the family Rikenellaceae (OR =1.27; 95% CI: 1.04- 1.55; P=0.02), the genus Eubacterium nodatum group (OR =1.13; 95% CI: 1.00-1.27; P=0.046), the genus Oxalobacter (OR =1.23; 95% CI: 1.06-1.43; P=0.006), the genus Parabacteroides (OR =1.41; 95% CI: 1.00-1.99; P=0.049), and the genus Sellimonas (OR =1.18; 95% CI: 1.03-1.35; P=0.02). No significant level pleiotropy or heterogeneity was detected in the IV, and there was no reverse causality between gut microbiota and malignant lymphoma. Conclusions: We investigated the potential causal relationship between gut microbiota and malignant lymphoma. Our findings provide a theoretical foundation for future research on the relationship between gut microbiota and lymphoma, and may facilitate the development of diagnostic, therapeutic, and preventive strategies for lymphoma in clinical practice.