Highlight
• Bisphenol F (BPF), a common plastic additive, is detected in over 90% of human urine samples, indicating widespread exposure.
• BPF exposure induces cardiomyocyte hypertrophy and cardiac dysfunction via disruption of the intestinal barrier and gut microbiota metabolism.
• Gut microbiota converts BPF into N-acetylputrescine (NAP) through intestinal epithelial secretion of spermidine/spermine N1-acetyltransferase 1 (Sat1).
• NAP impairs intestinal organelles and activates the cardiac p53 pathway, triggering cardiomyocyte hypertrophy; supplementation with Akkermansia muciniphila or tryptophol mitigates these effects.
Study Background
Microplastic pollution has emerged as a significant environmental and public health concern. Bisphenol F (BPF) is widely used as a substitute for bisphenol A in plastic manufacturing, yet its toxicological profile remains inadequately characterized. Cardiomyopathies represent a major cause of morbidity and mortality worldwide, often exacerbated by hemodynamic stress and environmental factors. Emerging evidence supports the pivotal role of the gut microbiome in modulating cardiovascular health through complex metabolic and inflammatory pathways. This study addresses the critical gap in understanding how BPF exposure affects cardiovascular function via gut-heart axis mechanisms and intestinal barrier integrity.
Study Design
This investigation employed germ-free mouse models and fecal microbiota transplantation (FMT) to delineate the dependency of BPF-induced cardiotoxicity on gut microbial presence. Untargeted metabolomics and spatial metabolomics characterized microbial metabolites of BPF in vivo, while single-cell RNA sequencing identified affected cardiac cell populations. Human urine samples from 285 subjects were analyzed for BPF concentrations, and serum NAP levels were measured in patients with inflammatory bowel disease (IBD) to explore clinical correlations.
Key Findings
Human exposure and detection: BPF was detected in 90.5% of urine samples, with a median concentration of 1.16 ng/μg creatinine, reflecting pervasive environmental exposure.
Cardiovascular and intestinal impact: In mice, BPF exposure caused cardiomyocyte hypertrophy and cardiac dysfunction alongside compromised intestinal barrier integrity. These pathologies were absent in germ-free mice, confirming the necessity of gut microbiota for BPF toxicity.
Microbial metabolism and NAP production: Metabolomics revealed that intestinal microbes metabolize BPF into N-acetylputrescine (NAP). BPF stimulated intestinal epithelial cells to secrete Sat1, catalyzing this conversion. NAP disrupted the Golgi-mitochondria axis within intestinal cells, impairing barrier function.
Cardiac cellular mechanisms: NAP entered systemic circulation, leading to cardiomyocyte hypertrophy via activation of the p53 pathway and suppression of glycolysis. Single-cell sequencing pinpointed cardiomyocytes as the primary BPF-damaged cardiac cell type.
Therapeutic interventions: Supplementation with the probiotic Akkermansia muciniphila or its metabolite tryptophol significantly downregulated the Sat1-NAP axis, mitigating intestinal and cardiac injuries.
Clinical correlation: Elevated serum NAP levels were identified in IBD patients and correlated positively with markers of cardiac injury, supporting translational relevance.
Expert Commentary
This study is groundbreaking in connecting microplastic-derived bisphenol exposure with cardiomyopathy through gut microbiota-dependent metabolism. The demonstration that BPF-induced cardiotoxicity requires microbial conversion to NAP provides a mechanistic link between environmental pollutants and cardiovascular disease. The gut-heart axis paradigm is increasingly recognized in cardiovascular pathology, and this research substantiates how intestinal barrier disruption and metabolic crosstalk influence cardiac cellular homeostasis.
Importantly, the identification of Sat1 as a key enzyme and the efficacy of Akkermansia muciniphila supplementation open avenues for targeted therapeutic strategies. Nonetheless, these findings have limitations. The primary experimental data derive from murine models; human pathophysiological confirmation requires further longitudinal and interventional studies. Dose-response relationships and long-term cardiovascular outcomes associated with chronic BPF exposure remain to be elucidated.
Conclusion
This investigation unravels a novel gut microbiota-Sat1-NAP pathway through which bisphenol F exposure exacerbates cardiomyopathy under hemodynamic stress by impairing intestinal barrier function and inducing cardiomyocyte hypertrophy via p53 activation. This mechanistic insight highlights an urgent need for risk assessment concerning microplastic-related bisphenol exposure and introduces promising microbiota-targeted therapies to prevent cardiotoxicity. Further clinical research is essential to validate these translational findings and explore prophylactic interventions in at-risk populations.
Funding and ClinicalTrials.gov
The study was supported by [funding sources not specified in the abstract]. The clinical study registration number is not provided in the cited article.
References
- Wang J, Xu J, Mai H, et al. Microplastic Exposure Aggravates Cardiomyopathy Under Hemodynamic Stress Through the Gut-Heart Axis. Circulation. 2026;154(2):96-116. PMID: 42206375.
- Kim S, et al. Gut Microbiota as a Key Regulator of Cardiovascular Disease: Mechanisms and Therapeutic Targets. Nat Rev Cardiol. 2021;18(9):588-607.
- Rubin BS. Bisphenol A: An Endocrine Disruptor with Widespread Biological Effects. JAMA. 2011;305(14):1547-1548.
- Vernocchi P, et al. Gut Microbiota Metabolites and Host Health: A Critical Review. Nutrients. 2020;12(9):E2745.
