Gut Microbiome, Immune Cells, and Heart Failure: A Multi-Omics Mendelian Randomization Study

Area of Science:

• Genomics
• Microbiology
• Immunology

Background:

• Heart failure (HF) presents a growing global health challenge with increasing prevalence and mortality.
• The gut microbiome is hypothesized to influence HF pathogenesis via immune system modulation.
• Identifying modifiable factors like the gut microbiome is crucial for understanding and treating HF.

Purpose of the Study:

• To investigate the causal relationship between gut microbial composition and heart failure (HF).
• To explore the role of the gut microbiome in HF pathogenesis through immune cell interactions.
• To identify potential microbial biomarkers and therapeutic targets for HF.

Main Methods:

• Two-sample Mendelian randomization (MR) analyses were performed using genome-wide association study (GWAS) data for gut microbes, immune cells, and HF.
• Single-cell and single-nucleus RNA sequencing data from HF patients and healthy controls were analyzed.
• Expression quantitative trait loci (eQTL) MR analysis integrated HF GWAS with heart eQTL data to identify candidate genes.
• Functional enrichment analysis was conducted to elucidate the biological pathways involved.

Main Results:

• Several gut bacterial genera, including Blautia, Corynebacterium, and Leclercia, were causally associated with an increased risk of HF.
• Other genera, such as CAG-125 and Fournierella, showed a protective effect against HF.
• Genus Leclercia exhibited a significant association with altered CD4+ T-cell counts, and HF patients displayed increased NK/T cells.
• eQTL MR analysis identified genes associated with HF risk and protective effects, enriched in pathways like IFN-γ response, PI3K/AKT/mTOR signaling, and angiogenesis.

Conclusions:

• This multi-omics MR study establishes a causal link between the gut microbiome, immune cells, and heart failure (HF).
• Alterations in T cells related to the genus Leclercia represent a potential focus for HF research and treatment.
• These findings provide novel insights into the mechanisms of gut microbiome-mediated HF and suggest new therapeutic avenues.