Association between Gut Microbiota and Leukemia: A Bidirectional Multivariable Mendelian Randomization Study

Background:

Empirical investigations have demonstrated a correlation between the gut microbiota and the onset and advancement of leukemia. However, inconsistencies in sequencing depths across studies and limited sample sizes within individual studies have contributed to inconclusive findings regarding changes in particular microbiota genera. The objective of this study is to investigate the potential bidirectional causal association between the gut microbiota composition and leukemia, and additionally to examine the potential of the gut microbiota in mitigating the risk of developing leukemia.

Method:

This multivariable Mendelian randomization (MVMR) study acquired top SNPs associated with the composition of gut microbiota (n=11,2958) and with leukemia [Chronic lymphocytic leukemia (CLL, n=16,380,466), chronic myelogenous leukemia (CML, n=456,348), Acute lymphoblastic leukemia (ALL, n=16,353,462), and Acute myeloid leukemia (AML, n=16,380,466)] from publicly available genome-wide association studies (GWAS). The SNPs estimates were pooled using inverse-variance weighted (IVW) meta-analysis, with sensitivity analyses-weighted median (WM), MR Egger, and MR Pleiotropy Residual Sum and Outlier (PRESSO). Finally, reverse MR analysis was performed to evaluate the possibility of reverse causation.

Results:

The Clostridia class (OR=0.13, 95%CI=0.02-0.85), Peptococcaceae family (OR=0.20, 95%CI=0.05-0.86), Clostridiales order (OR=0.11, 95%CI=0.02-0.66) and Firmicutes phylum (OR=0.15, 95%CI=0.03-0.78) had protective causal effects on acute leukemia (AL). In contrast, the Gammaproteobacteria class (OR=29.95, 95%CI=3.01-297.89), Veillonellaceae family (OR=4.39, 95%CI=1.23-15.62), Eubacterium genus, Oxidoreducens group (OR=4.78, 95%CI=1.13-20.29), Lactococcus genus (OR=2.85, 95%CI=1.09-7.45) and Slackia genus (OR=6.76, 95%CI=1.45-31.41) were risk factors for AL. This study also shown a protective effect of Lachnospiraceae ND3007 group (OR=0.14, 95%CI=0.02-0.96), Desulfovibrio genus (OR=0.41, 95%CI=0.18-0.95) and Eggerthella genus (OR=0.47, 95%CI=0.26-0.87) on chronic leukemia (CL). Additionally, Methanobacteria class, Methanobacteriaceae family, Methanobacteriales order, Erysipelatoclostridium genus, and Flavonifractor genus, all shown an anti-protective effect on CL (P <0.05). Bidirectional MVMR showed that AL and ML also has an effect on the gut microbiota.

Conclusion:

This MVMR study showed a protective effect of Clostridia class, Peptococcaceae family, Clostridiales order and Firmicutes phylum, and a potentially anti-protective effect of Gammaproteobacteria class, Veillonellaceae family, Eubacterium genus oxidoreducens group, Lactococcus genu and Slackia genus on AL. The results also show that several groups of gut microbiotas are anti-protective against CL. We also observed a reverse causal link between leukemia and gut microbiota. Further studies are needed to transform the findings into practice and required to show how the gut microbiota affects the development of leukemia.

Key Words: Gut microbiota; Chronic lymphocytic leukemia; chronic myelogenous leukemia; Acute lymphoblastic leukemia; Acute myeloid leukemia; Multivariable Mendelian randomization