Gut Bacteria F. prausnitzii Shields Aging Hearts by Blocking Iron-Driven Cell Death

Heart failure (HF) disproportionately burdens older adults, yet the mechanisms linking biological aging to cardiac decline remain incompletely understood. This study bridges a critical gap by implicating age-related gut microbiota dysbiosis—specifically the loss of Faecalibacterium prausnitzii—as a causal driver of HF through ferroptosis, an iron-dependent, lipid-peroxidation-mediated form of programmed cell death.

The researchers began with bioinformatic analysis of a publicly available single-cell RNA sequencing dataset, identifying markedly elevated ferroptosis activity in cardiomyocytes of elderly versus young individuals. They then validated this finding in 18-month-old rats treated with the ferroptosis inhibitor ferrostatin-1 (0.8 mg/kg intraperitoneally, weekly for 4 months), which significantly reduced cardiac ferroptosis markers and preserved cardiac ejection fraction and fractional shortening. This established ferroptosis as a functional mediator of age-related cardiac dysfunction.

To causally link gut microbiota to cardiac ferroptosis, the team performed fecal microbiota transplantation (FMT) from aged rats or elderly HF patients into antibiotic-pretreated young rats. Recipients of aged or HF-derived microbiota developed cardiac dysfunction and elevated ferroptosis, effects that were rescued by co-treatment with ferrostatin-1. 16S rRNA sequencing and PCR quantification of human stool samples (40 elderly healthy controls, 40 elderly HF patients) consistently revealed substantial depletion of F. prausnitzii in elderly subjects, with the greatest decline in HF patients.

Oral gavage of F. prausnitzii (1×10⁹ CFU, three times weekly) in D-galactose-induced aging rats significantly improved cardiac function and suppressed ferroptosis. Crucially, a genetically engineered BCoAT-knockout F. prausnitzii strain incapable of producing butyrate failed to confer these benefits, confirming butyrate as the active mediator. Restoring butyrate alongside the mutant strain rescued the cardioprotective effect. Sodium butyrate administered in drinking water (1% w/w) similarly attenuated cardiac dysfunction in aging rats. Mechanistically, butyrate reduced intracellular iron accumulation in senescent cardiomyocytes by downregulating lipocalin-2 (LCN2), an iron-transport protein that promotes ferroptotic susceptibility when overexpressed.

These findings collectively define an actionable gut–heart axis: aging depletes F. prausnitzii → butyrate production falls → LCN2 rises in cardiomyocytes → iron accumulates → ferroptosis drives cardiac dysfunction. The study proposes F. prausnitzii supplementation or butyrate administration as practical, microbiome-targeted strategies for preventing or treating age-related HF. Notable caveats include reliance on male rats only (females are resistant to iron-overload cardiomyopathy), a single chemically induced aging model (D-galactose), and the need for human interventional trials to confirm translatability.