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

The global burden of heart failure is escalating, marked by persistently rising prevalence, incidence, and mortality. The emerging hypothesis that the gut microbiome, as a modifiable factor, influences HF pathogenesis through immune modulation.

To examine the causal relationship, we conducted two-sample Mendelian randomization (MR) analyses using summary genetic data, which was obtained from genome-wide association studies (GWASs) of gut microbial taxa, immune cells, and HF. Single-cell RNA sequencing data and single-nucleus RNA sequencing from chronic heart failure and healthy samples were extracted for investigation. Expression quantitative trait loci (eQTL) MR analysis was used to integrate HF GWAS with eQTL from heart to confirm potential genes. We performed functional enrichment analysis to enrich their functions.

The analysis revealed that genus Blautia (p = 0.0287), genus Corynebactrium (p = 0.022), genus Demequina (p = 0.0064), genus Enterococcus (p = 0.0307), genus Eubacterium (p = 0.0234), genus F0482 (p = 0.0107), genus Leclercia (p = 0.0026), genus Prevotellamassilia (p = 0.0444), and genus Ruminococcus were causally linked to a higher risk of HF, while genus CAG-125 (p = 0.0443), genus CAG-245 (p = 0.0116), genus Fournierella (p = 0.0326), genus Roseibacillus (p = 0.028) protective factors for HF. Among differential microflora, genus Leclercia was significantly related to higher level of HVEM on terminally differentiated CD4+T-cell count (p = 0.0058). Moreover, HF patients underwent obviously increased NK/T cells. We identified positive association of EIF3A, RPL5, SLC25A51, HERC5, SUSD3, ZNF292, ZNF655, and DNAJC9 with increased risk of HF, whereas the expression of RMC1, CAMK2G, RPS26, ATP5PO displayed protective effect against HF by eQTL MR analysis; they were mainly enriched in myc-Targets-V1, IFN-γ-response, IFN-α-response, PI3K/AKT/mTOR signaling, TGF-beta signaling, allograft rejection, notch signaling pathways, angiogenesis, epithelial mesenchymal transition, UV-response-DN, hedgehog signaling, myogenesis.

Our multi-omics MR study uncovered the causality of gut microbiome on immune cells and HF. Genus Leclercia-related changes in T cells may present as a viable focus for HF. This offers new insights into mechanisms and therapy of gut microbiome-mediated HF.