Indole-3 Acetate Limits Dysbiosis-Driven Diastolic Failure via Hcrt Neurons

The nervous, gastrointestinal, renal, and cardiovascular systems orchestrate ion-fluid homeostasis and impose reciprocal adaptations to hypertensive challenges. Mechanistic insight into the interorgan crosstalk is fundamental for tackling pathogenesis of hypertensive heart disease.

We integrated gut microbiome profiling and targeted metabolomics in a zebrafish model of ion dyshomeostasis-induced diastolic dysfunction to identify microbial metabolites linked to hypertensive cardiac remodeling. To dissect the gut-brain-heart axis, we depleted microbiota, supplemented specific microbial metabolites, and chemogenetically ablated hypothalamic neurons. Neuronal activity was monitored using in vivo calcium imaging and immunohistochemistry, and cardiovascular function was assessed by live imaging. Patient serum metabolic profiles were analyzed to evaluate relevance to human hypertension.

Zebrafish larvae exposed to ion dyshomeostasis exhibited gut dysbiosis, marked by reduced microbial richness and diversity, particularly among indole- and indole-3-producing taxa. Functionally, commensal microbiota protected against cardiovascular structural and functional remodeling during hypertensive challenge, whereas antibiotic-induced perturbation worsened hemodynamic parameters of arterial hypertension and impaired ventricular relaxation. Gut metabolomics identified a lower abundance of indole-3 acetic acid as a key signature of the hypertensive response, a pattern conserved in serum metabolome from patients with hypertension. Indole-3 acetic acid supplementation, acting via the aryl hydrocarbon receptor, mitigated cardiac concentric hypertrophy and diastolic dysfunction. These effects involved hypothalamic hypocretin neurons, with indole-3 acetic acid suppressing their overactivation and the associated sympathetic overdrive in cardiac-projecting paravertebral ganglia during the hypertensive challenge. Indole-3 acetic acid also prevented renin-angiotensin-aldosterone system upregulation, indicating that it operates upstream of both autonomic and hormonal pathways.

Our findings uncover a gut-brain-heart crosstalk where hypertensive gut dysbiosis signals to the central nervous system to drive diastolic remodeling. Modulation of indole-3 acetic acid signaling and hypocretin neuron activity represents a promising strategy to counter the multisystemic pathogenesis of hypertensive heart disease.