The relationship between gut microbiota, plasma metabolites, and iron deficiency anemia in European populations: a three-sample Mendelian randomization analysis.

Objectives: Previous research indicates that gut microbial composition significantly affects iron metabolism and absorption, potentially influencing the risk of iron deficiency anemia (IDA). This study aimed to investigate how plasma metabolites might mediate the relationship between gut microbiota and IDA.

Methods: We performed MR analyses utilizing publicly available genome-wide association study (GWAS) data, comprising 5,959 individuals for gut microbiota characterization and 8,299 individuals for plasma metabolite profiling. Outcome data for IDA were sourced from large-scale cohorts including Pan-UKB, FinnGen, and GERA, collectively encompassing 28,075 IDA cases and 857,930 controls. We assessed the mediating role of identified plasma metabolites on the relationship between gut microbial taxa and IDA using the product-of-coefficients method.

Results: Our analyses identified 18 gut bacterial taxa and numerous plasma metabolites with potential causal links to IDA. For example, genetically higher abundance of species Ruminococcus E sp003521625 increased IDA risk (OR  =  1.20; 95 % CI  =  1.04-1.39; P  =  0.011), whereas higher abundance of family Jiangellaceae decreased risk (OR  =  0.77; 95 % CI  =  0.61-0.98; P  =  0.035). Mediation analyses revealed that the metabolite 1-palmitoyl-2-stearoyl-glycero-3-phosphocholine (PSPC) significantly mediated the Jiangellaceae - IDA association, with an indirect effect of -0.0477 (95 % CI  =  -0.0952 to -0.0001; P  =  0.049) accounting for approximately 18.55 % of the total effect.

Conclusion: Our findings validate the crucial role of gut microbiota in IDA etiology, highlighting mediation via key plasma metabolites. These insights enhance understanding of the gut microbiota-hematopoiesis axis and offer potential avenues for novel biomarkers or therapeutic interventions targeting IDA.