Gut microbiome shifts in chronic systolic heart failure are associated with disease severity and clinical improvement.

The contribution of the gut microbiome to chronic heart failure (HF) remains poorly defined. We performed integrated microbiome and host multi-omic profiling of adults with chronic systolic HF due to nonischemic cardiomyopathy (n = 59) and healthy participants (n = 50), including longitudinal sampling in some cases. Here we show that patients with HF have depletion of anti-inflammatory Bifidobacterium and reduced short-chain fatty acid biosynthetic potential, alongside altered microbiome-immune system interactions. Longitudinal analysis revealed that higher Bifidobacterium abundance was associated with clinical improvement. Multi-omic integration prioritized indole-3-propionic acid (IPA), a gut metabolite with cardioprotective properties, as a candidate mechanistic link. We confirmed that Bifidobacterium species can produce IPA in vitro and circulating IPA levels were associated with milder HF severity. Together, these findings define gut microbiome alterations in chronic systolic HF, identify candidate microbiome biomarkers of disease severity and trajectory, and suggest microbiome-derived metabolites as potential therapeutic targets.