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Published on: November 10, 2023
The Causal Role of the Gut Microbiota-Plasma Metabolome Axis in Myeloproliferative Neoplasm Pathogenesis: A Mendelian
Background:
Myeloproliferative neoplasms (MPN), a group of chronic hematologic neoplasms, are driven by inflammatory mechanisms that influence disease initiation and progression. Emerging evidence highlights the gut microbiome and plasma metabolome as pivotal immunomodulators, yet their causal roles in MPN pathogenesis remain uncharacterized.
Methods:
We conducted a two-sample Mendelian randomization (MR) analysis to systematically evaluate causal relationships between 196 gut microbial taxa, 526 plasma metabolites, and MPN risk. Instrumental variables were derived from genome-wide association studies (GWASs) of microbial/metabolite traits. Validation utilized 16S rRNA sequencing data from NCBI Bioproject PRJNA376506. Mediation and multivariable MR analyses elucidated metabolite-mediated pathways linking microbial taxa to MPN.
Results:
Our MR analysis revealed that 7 intestinal taxa and 17 plasma metabolites are causally linked to MPN. External validation confirmed the three taxa's differential abundance in MPN cohorts. Mediation analysis revealed two mediated relationships, of which succinylcarnitine mediated 14.5% of the effect, and lysine 27.9%, linking the Eubacterium xylanophilum group to MPN. Multivariate MR analysis showed that both succinylcarnitine (p = 0.004) and lysine (p = 0.040) had a significant causal effect on MPN.
Conclusions:
This study identifies novel gut microbiota-metabolite axes driving MPN pathogenesis through immunometabolic mechanisms. The validated biomarkers provide potential therapeutic targets for modulating inflammation in myeloproliferative disorders.
Insights
This study reveals how gut microbes and metabolites causally influence myeloproliferative neoplasms (MPN) through inflammation. Specific microbial-metabolite pathways, like Eubacterium xylanophilum group linked to succinylcarnitine and lysine, offer new therapeutic targets for MPN.
Area of Science:
- Hematology
- Immunology
- Microbiome Research
Background:
- Myeloproliferative neoplasms (MPN) are chronic blood cancers driven by inflammation.
- The gut microbiome and plasma metabolome are implicated as key immune modulators in MPN.
- Causal links between the gut microbiome, metabolome, and MPN pathogenesis require further investigation.
Purpose of the Study:
- To investigate the causal relationships between gut microbial taxa, plasma metabolites, and MPN risk.
- To identify specific microbial and metabolic pathways contributing to MPN development.
Main Methods:
- A two-sample Mendelian randomization (MR) analysis was performed.
- Genome-wide association study (GWAS) data for microbial and metabolite traits were used.
- Validation involved 16S rRNA sequencing, mediation, and multivariable MR analyses.
Main Results:
- Seven intestinal taxa and 17 plasma metabolites were found to be causally linked to MPN.
- Succinylcarnitine and lysine mediated the effect of the Eubacterium xylanophilum group on MPN.
- Both succinylcarnitine and lysine demonstrated a significant causal effect on MPN risk.
Conclusions:
- Novel gut microbiota-metabolite axes driving MPN pathogenesis via immunometabolic mechanisms were identified.
- Validated biomarkers, such as succinylcarnitine and lysine, present potential therapeutic targets.
- Modulating these pathways could offer new strategies for treating myeloproliferative disorders.
