Hypertensive gut dysbiosis reduces indole-3 acetic acid, which normally suppresses hypothalamic hypocretin neuron overactivation and sympathetic overdrive, and restoring indole-3 acetic acid signaling via the aryl hydrocarbon receptor mitigates cardiac concentric hypertrophy and diastolic dysfunction.
Key Findings
Results
Zebrafish larvae exposed to ion dyshomeostasis exhibited gut dysbiosis characterized by reduced microbial richness and diversity, particularly among indole- and indole-3-producing taxa.
A zebrafish model of ion dyshomeostasis-induced diastolic dysfunction was used for gut microbiome profiling and targeted metabolomics.
Dysbiosis was marked by reduced microbial richness and diversity specifically among indole- and indole-3-producing bacterial taxa.
This model was used to identify microbial metabolites linked to hypertensive cardiac remodeling.
Results
Commensal microbiota protected against cardiovascular structural and functional remodeling during hypertensive challenge, while antibiotic-induced microbiota perturbation worsened hemodynamic parameters and impaired ventricular relaxation.
Microbiota depletion experiments were used to dissect the gut-brain-heart axis.
Antibiotic-induced perturbation worsened hemodynamic parameters of arterial hypertension.
Antibiotic treatment also impaired ventricular relaxation, indicating diastolic dysfunction.
These findings established a functional role for the microbiota in protecting against hypertensive cardiac remodeling.
Results
Gut metabolomics identified lower abundance of indole-3 acetic acid (IAA) as a key metabolic signature of the hypertensive response in zebrafish, a pattern conserved in serum metabolomes from patients with hypertension.
Targeted metabolomics was integrated with gut microbiome profiling in the zebrafish model.
Reduced indole-3 acetic acid was identified as a key signature of the hypertensive response.
Patient serum metabolic profiles were analyzed to evaluate relevance to human hypertension.
The reduction in IAA observed in zebrafish was conserved in the serum metabolome of human hypertension patients.
Results
Indole-3 acetic acid supplementation, acting via the aryl hydrocarbon receptor, mitigated cardiac concentric hypertrophy and diastolic dysfunction in the zebrafish hypertensive model.
IAA was supplemented exogenously in zebrafish subjected to ion dyshomeostasis-induced hypertensive challenge.
The protective effects of IAA were mediated via the aryl hydrocarbon receptor (AhR) signaling pathway.
IAA supplementation mitigated both cardiac concentric hypertrophy and diastolic dysfunction.
Cardiovascular function was assessed by live imaging.
Results
Indole-3 acetic acid suppressed overactivation of hypothalamic hypocretin neurons and the associated sympathetic overdrive in cardiac-projecting paravertebral ganglia during hypertensive challenge.
Hypothalamic neurons were chemogenetically ablated to dissect the gut-brain-heart axis.
Neuronal activity was monitored using in vivo calcium imaging and immunohistochemistry.
IAA specifically suppressed overactivation of hypocretin (Hcrt) neurons in the hypothalamus.
IAA also reduced the associated sympathetic overdrive in cardiac-projecting paravertebral ganglia.
These findings implicated a gut-brain-heart axis involving central nervous system hypocretin neuron activity.
Results
Indole-3 acetic acid prevented upregulation of the renin-angiotensin-aldosterone system (RAAS), indicating it operates upstream of both autonomic and hormonal pathways.
RAAS upregulation was assessed during the hypertensive challenge in the zebrafish model.
IAA supplementation prevented RAAS upregulation.
This finding indicates that IAA acts upstream of both the autonomic (sympathetic) and hormonal (RAAS) pathways involved in hypertensive remodeling.