Causal Relationship between Gut Microbiota, Derived Metabolites, and Diffuse Large B-Cell Lymphoma: A Two-Sample Mendelian Randomization Study

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Introduction: The human gastrointestinal tract contains approximately one hundred trillion microorganisms that provide numerous benefits, including energy absorption, protection against pathogens, and regulation of the immune system. Alterations in the gut microbiota, known as dysbiosis, can disrupt these normal physiological processes and have been associated with adverse conditions such as inflammatory states, immune dysregulation, and even malignancies. Studies have shown that the gut microbiota of patients with diffuse large B-cell lymphoma (DLBCL) differs significantly from that of healthy individuals, and changes in the abundance of specific gut microbiota contributes to the prognosis of DLBCL patients. Certain microbiota could regulate the development of DLBCL through their metabolites. However, these case-control studies are susceptible to confounding factors such as age, environment, lifestyle, other diseases, and treatments, which may bias the results. Herein, we employ Mendelian randomization (MR) to investigate the causal relationships between gut microbiota, derived metabolites, and DLBCL. Methods: Gut microbiota data were sourced from the MiBioGen consortium, metabolite information from the TwinsUK and KORA studies, and DLBCL-related data from FinnGen. The single nucleotide polymorphisms (SNPs) were used to serve as instrumental variables (IVs). The primary method for our MR analysis was inverse-variance weighting, enhanced by MR-Egger regression, weighted median, simple mode and weighted mode methods to investigate the causal impacts of the gut microbiome and derived metabolites on DLBCL. We also employed reverse MR analysis to explore the causal effect of DLBCL on gut microbiota. The results underwent verification through a series of sensitivity analyses, including Cochran's Q test, the MR-Egger regression test, and the MR-PRESSO test. Additionally, Bayesian Mendelian randomization (BWMR) was used to further substantiate the findings. Result: Our results indicated that three genus and two microbiome-derived metabolites were causally related to DLBCL. Additionally, reverse MR analysis revealed that DLBCL had a causal relationship with one class, one order, one family, and two genus. Specifically, Alistipes (P=0.013) and Ruminococcaceae UCG011 (P=0.034) were associated with a reduced risk of DLBCL, while Bilophila (P=0.031) was linked to an increased risk. Further reverse MR analysis indicated that DLBCL contributed to a reduction in the abundance of the class Deltaproteobacteria (P=0.037), order Desulfovibrionales (P=0.041), family Oxalobacteraceae (P=0.031), and genus Oxalobacter (P=0.024), along with an increase in the abundance of genus Anaerofilum (P=0.031). The study also found that indolepropionate (P=0.003) decreased the risk of DLBCL, while 7-alpha-hydroxy-3-oxo-4-cholestenoate (P=0.02) increased the risk. Comprehensive sensitivity analyses, including Cochran's Q test, MR-Egger regression test, and MR-PRESSO test, did not identify any outliers, underscoring the reliability of our findings. Moreover, a leave-one-out analysis confirmed that no single SNP disproportionately influenced the MR estimates, further validating the robustness and reliability of our results. Conclusion: Our results provide evidence supporting a potential causal relationship between gut microbiota, derived metabolites, and DLBCL, thus opening new avenues for exploring the pathogenesis of DLBCL and its potential applications in diagnosis and treatment. Keywords: Mendelian randomization; gut microbiota; metabolites; diffuse large B-cell lymphoma; SNPs. Disclosures: No relevant conflicts of interest to declare. Category: Aggressive Lymphomas: Clinical and Epidemiological

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