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 to MPN. Multivariate MR analysis showed that both succinylcarnitine ( = 0.004) and lysine ( = 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.