Utilizing MR analysis, the present study aimed to explore the potential causal relationship between GM taxa and seven common hematological malignancies, namely MM and related plasma cell neoplasms, ML, LL, FL, HL, DLBCL, and MPN. Surprisingly, the results revealed a significant causal association between the genetic predisposition to the family Oxalobacteraceae and an elevated risk of ML. Additionally, the study identified 22 GM taxa that could potentially act as risk factors for hematological malignancies.
Previously, literature about family Oxalobacteraceae was extremely limited. It has been reported that Oxalobacter could degrade dietary oxalate and metabolize oxalate by the gut mucosa(Miller et al., 2019). Oxalate metabolism imbalances can cause severe harm to the body, including systemic and localized inflammation, cardiovascular complications, and chronic kidney disease and kidney failure(Ermer et al., 2023; Abratt and Reid, 2010; Ticinesi et al., 2018). A recent MR study among Chinese and European populations has revealed that Oxalobacter is related to increased odds of longevity(Liu et al., 2023). At the same time, according to a microbiota-related gene set enrichment analysis, the family Oxalobacteraceae appeared to be linked to six autoimmune diseases, including osteoporosis, celiac disease, type 1 diabetes, inflammatory bowel diseases, primary biliary cirrhosis, multiple sclerosis and primary sclerosing cholangitis(Cao et al., 2021). There have been no investigations on the association between family Oxalobacteraceae and ML; nonetheless, the underlying mechanism deserves more exploration. Further pathways from family Oxalobacteraceae to ML could be expected in future studies.
In addition to the significant estimates above, our research also identified nominal significant associations between GMs and hematological malignancies. Although the observed associations did not reach Bonferroni corrected significance, the potential influence of these GMs should not be ignored. Instead, these results might point to a potential bacterial composition that contributes to hematological malignancies, which would help in determining the risk of hematological malignancies and provide candidates for bacteria that might have implications for researchers to focus on specific GM taxa in future studies.
Although the mechanisms underlying the relationship between GMs and hematologic malignancies are not yet fully understood, some evidence suggests that they may play an important role. (i) Jian et al. reported that some nitrogen-recycling GMs such as Klebsiella and Streptococcus can provide a nitrogen source to meet the energy requirements of MM cells for L-glutamine(Gln) synthesis and rapid proliferation, thereby accelerating MM(Jian et al., 2020). (ii) GMs have been shown in studies to alter the levels of gut-derived metabolites such as short-chain fatty acids (SCFAs), which can suppress the secretion of inflammatory cytokines and the activation of nuclear factor κB signaling pathways, resulting in lower the levels of inflammatory factors in the bone marrow microenvironment and the suppression of the progression of hematologic malignancies(Lu et al., 2022). (iii) In addition, it was found that GMs facilitated the progression of acute myeloid leukemia (AML) by modulating the intestinal barrier function via butyrate. The analysis of SCFAs metabolome demonstrated a reduction in butyrate levels in the intestinal contents of AML patients, leading to impairment of the intestinal barrier and elevated absorption of lipopolysaccharide (LPS) into the bloodstream. Moreover, the heightened levels of LPS exacerbated the development of AML, while the addition of intestinal butyrate preserved the integrity of the intestinal mucosa and mitigated the severity of AML(Wang et al., 2022).
This is the first study to examine the causal relationship between GMs and hematologic malignancies using MR analysis. The study has several strengths, the first of which is that MR analyses are less susceptible to confounding and reverse causality not observed in observational studies. Secondly, through various sensitivity analyses using different MR methods and different model assumptions, the results are consistent, indicating that the results are robust and persuasive.
There are some limitations to our study. Our sample data were all derived from European ancestry, and while this may reduce the potential bias due to demographic stratification, our findings may not be extrapolated to other populations. In addition, due to the relatively small number of cases of hematologic malignancies, it is imperative to conduct future analyses based on a larger sample size of GWAS summary data in order to enhance the robustness and reliability of the findings.