Sumary: High blood pressure and heart failure might be managed through the gut. New research has identified a direct communication line between gut bacteria, the brain, and the heart. The study reveals that a specific bacterial metabolite called indole-3 acetic acid (IAA) acts as a brake on “stress” neurons in the brain’s hypothalamus.
When IAA levels are low, these neurons become overactive, causing the heart muscle to stiffen—a condition known as diastolic dysfunction. This discovery suggests that diet, probiotics, or IAA supplementation could become powerful new tools for preventing hypertension and heart failure.
Key Facts
- The IAA Brake: Gut microbes produce indole-3 acetic acid (IAA) from the amino acid tryptophan. IAA travels to the brain to regulate hypocretin (Hcrt) neurons.
- Brain as a Hub: Hcrt neurons in the hypothalamus act as the central switch. Without enough IAA, these neurons overfire, sending sympathetic nerve signals that stiffen the heart.
- Diastolic Dysfunction: This research helps explain why the heart struggles to relax in millions of patients—a key driver of heart failure with preserved ejection fraction (HFpEF).
- Human Connection: A study of human patients showed that those with hypertension have lower IAA levels, with a particularly strong effect seen in hypertensive women.
- Biomarker Potential: IAA levels in the blood could serve as an early warning signal for people at high risk of heart failure, allowing for preventative dietary changes.
Source: MDC
Hypertension and heart failure affect millions worldwide. Yet in many patients, doctors cannot fully explain why the heart becomes stiff and struggles to relax – a condition known as diastolic dysfunction.
Researchers in the lab of Dr. Suphansa Sawamiphak, Group Leader of Cardiovascular-Hematopoietic Interaction at the Max Delbrück Center, have identified a direct communication line between gut bacteria, the brain, and the heart.
Using zebrafish as a model, the team discovered that certain gut microbes produce a small molecule called indole-3 acetic acid (IAA) from the dietary amino acid tryptophan. IAA acts on neurons in the brain, which in turn, control the heart. The study was published in “Circulation Research.”
“We were surprised that a single bacterial metabolite could influence the central nervous system, the heart, and major hormonal systems at the same time,” says Bhakti Zakarauskas-Seth, lead author of the paper. “It shows that the brain can act as a central hub in gut-heart communication.”
Tracking a signal from gut to brain
To understand how gut bacteria might influence the heart, the researchers focused on a distinct group of neurons in the hypothalamus known as hypocretin (Hcrt) in zebrafish larvae. These cells produce Hcrt neuropeptides, also known as orexins, regulate many involuntary functions in the body, such as sleep and eating patterns, but also heart activity.
When IAA levels dropped, Hcrt neurons became overactive. This increased sympathetic nerve signals to the heart, causing the heart muscle to stiffen, impairing its ability to relax properly.
When the researchers supplemented the larvae with IAA, neuronal activity normalized, heart function and blood pressure improved, and even related hormones such as renin and angiotensinogen returned to healthier levels.
They then examined data from a cohort of patients – humans also have Hcrt neurons – and found that IAA levels were reduced in patients with hypertension. Notably, they observed a sex-specific effect, with hypertensive women showing significantly lower levels of IAA in their serum samples than men.
Implications for patients and prevention
Diastolic dysfunction very common – up to half of all people over age 70 have some level of impairment. It is also is the underlying functional mechanism of heart failure with preserved ejection fraction (HFpEF), which accounts for over 50% of all heart failure cases.
For these patients, the findings open several potential avenues for better care, says Zakarauskas-Seth.
“IAA levels could serve as a biomarker to identify patients at high risk of hypertension or heart failure. Therapeutically, boosting IAA production – for example through diet, probiotics, or supplementation – could become a new strategy to prevent or treat cardiovascular disease.”
That a single bacterial metabolite can influence the central nervous system, the heart, and major hormonal system also underscores a broader message, she adds.
“The body does not operate in isolated compartments. Gut health, microbial balance, and diet directly shape how well the heart functions.”
The researchers will need to validate their findings in other animal models and clinical studies will be needed to determine whether restoring IAA can benefit patients.
Key Questions Answered:
A: It uses the brain as a middleman! Your gut bacteria produce a chemical called IAA from the food you eat. This chemical tells your brain to stay calm. If your gut doesn’t produce enough IAA, your brain gets “stressed” and sends signals that make your heart stiff and your blood pressure rise.
A: The study suggests that foods rich in tryptophan (like turkey, eggs, and cheese) might help, as gut bacteria turn tryptophan into IAA. However, the key is having the right microbes to do the work. Probiotics or IAA supplements could be the future of heart care.
A: The researchers found that hypertensive women had significantly lower levels of IAA than men. This suggests that the gut-brain-heart connection might play a particularly crucial role in cardiovascular health for women.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neuroscience research news
Author: Gunjan Sinha
Source: MDC
Contact: Gunjan Sinha – MDC
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Indole-3 acetate limits dysbiosis-driven diastolic failure via Hcrt neurons” by Bhakti I. Zakarauskas-Seth, Giovanni Forcari, Harithaa Anandakumar, Ilan Kotlar-Goldaper, Clara Barraud, Nina Jovanovic, Ulrike Brüning, Jennifer Kirwan, Nicola Wilck, Sofia K. Forslund, Dominik N. Müller, Alessandro Filosa, and Suphansa Sawamiphak. Circulation Research
DOI:10.1161/CIRCRESAHA.125.326990
Abstract
Indole-3 acetate limits dysbiosis-driven diastolic failure via Hcrt neurons
BACKGROUND:
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.
METHODS:
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.
RESULTS:
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.
CONCLUSIONS:
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.
