A Mendelian randomization study with bioinformatics analysis reveals gut microbiota mediates in heart failure and Alzheimer's disease via BAFF-R.

BACKGROUND

The causal relationship between heart failure (HF) and Alzheimer's Disease (AD) is still debated, and the mechanisms underlying AD caused by HF are still not fully understood.

METHODS

This study aimed to explore the potential genetic causality between HF and AD using two-sample Mendelian randomization (MR) study. The investigation was extended with mediation MR to explore the underlying genetic mechanisms. Bioinformatics analysis provided additional evidence.

RESULTS

In our investigation, we harnessed a two-sample MR method to delineate a causal relationship between HF and AD, uncovering a significant positive association. Our results, derived from a meticulous two-step MR analysis, have shed new light on the mediating role of gut microbiota (GM) within the HF-AD interplay. Notably, we identified specific metabolic pathways with substantial correlations: a pivotal super-pathway crucial for the biosynthesis of branched chain amino acids (BCAAs) and the pyrimidine deoxyribonucleotides de novo biosynthesis II pathway. Our findings extend beyond the metabolic, revealing the 'BAFF-R on CD20-' immune cells as key mediators in the GM-AD pathway. Bioinformatics analysis revealed significant enrichment of common differentially expressed genes between HF and AD in immune-related pathways.

CONCLUSIONS

We present a thorough genetic analysis of the relationship between HF, AD, and the intestinal-neuroimmune interaction, emphasizing the potential of GM and immune cells as therapeutic targets.