Targeting the Gut–Kidney–Brain Axis: Precision Nutrition and Microbial Metabolites as Novel Therapeutics for Hypertension

Abstract

Hypertension remains the leading modifiable risk factor for global cardiovascular mortality, yet a significant proportion of patients exhibit suboptimal responses to conventional therapies. Recent discoveries highlight the gut microbiome as a central regulator of blood pressure (BP) via the gut–kidney–brain axis. Microbial metabolites—including short-chain fatty acids (SCFAs) and trimethylamine-N-oxide (TMAO)—modulate vascular tone, renal sodium handling, immune signaling, and systemic inflammation. This review synthesizes evidence on how diet, microbial composition, and metabolite profiles converge to influence BP regulation. We highlight the transition from population-based dietary recommendations toward precision nutrition, emphasizing dietary fibers, polyphenols, proteins, and fats as modulators of microbial metabolism. Microbiome-directed strategies such as probiotics, prebiotics, and fecal microbiota transplantation (FMT) are also explored. By integrating the holobiont concept, this review proposes microbiome-targeted interventions as a foundational approach to hypertension prevention and treatment, paving the way for precision cardiovascular medicine.

Introduction

Cardiovascular disease (CVD) remains the leading cause of global mortality, with hypertension contributing to more than 9 million deaths annually [1,2]. Low- and middle-income countries (LMICs) bear a disproportionate burden, accounting for over 80% of CVD-related deaths [3]. In Kenya, prevalence estimates of hypertension range between 12–23%, with awareness, treatment, and control rates remaining alarmingly low [4–6]. Barriers include limited access to diagnostics, cost of medications, and weak health infrastructure.Traditional pharmacological therapies remain essential, yet resistant hypertension and poor long-term adherence underscore the need for complementary strategies. Over the last decade, a paradigm shift has occurred: hypertension is no longer viewed solely as a hemodynamic or renal disorder, but as a systemic condition influenced by gut microbial ecology. The human body functions as a holobiont, where microbial communities generate metabolites that act as signaling molecules, shaping vascular, renal, and neuro-immune physiology [7–9]. Dysbiosis is increasingly recognized as a causal factor in hypertension, mediated by pro-inflammatory metabolites and barrier dysfunction. This review evaluates how dietary modulation of the microbiome influences BP and considers precision nutrition as a frontier in hypertension therapy.

The Gut Microbiome as a Blood Pressure Regulator

The gut microbiome acts as a virtual endocrine organ, producing metabolites that interact with host receptors across multiple systems.

SCFAs (acetate, propionate, butyrate): Generated from dietary fiber fermentation, these molecules lower BP via G-protein coupled receptors (GPR41/43, Olfr78), leading to vasodilation, renin–angiotensin modulation, and reduced inflammation.
TMAO: Derived from microbial metabolism of dietary choline and L-carnitine, TMAO promotes vascular dysfunction, oxidative stress, and inflammation, contributing to hypertensive and atherogenic phenotypes.
Barrier dysfunction and immune activation: Dysbiosis increases intestinal permeability, enabling lipopolysaccharide (LPS) translocation, Th17 activation, and systemic inflammation—all drivers of hypertension.

Thus, the microbiome integrates dietary cues with renal and neurovascular regulation, positioning it as a therapeutic target.

Dietary Levers for Microbiome-Mediated Blood Pressure Control

Carbohydrates – Refined sugars and ultra-processed foods: Promote dysbiosis, leaky gut, and pro-inflammatory signaling.Complex carbohydrates and fibers: Enhance SCFA production and support BP-lowering genera such as Faecalibacterium and Roseburia.
Proteins – Animal proteins (red/processed meat): Substrates for TMAO production.Plant proteins (soy, legumes, peas): Promote SCFA generation, improve microbial diversity, and provide bioactive peptides with vasoprotective properties.
Fats –Saturated/trans fats: Reduce microbial diversity and promote inflammation.Unsaturated fats (olive oil, nuts, fish): Support anti-inflammatory microbes and SCFA-producing pathways.
Polyphenols – Poorly absorbed directly, but metabolized by microbes into vasodilatory and antioxidant metabolites. Found in berries, green tea, garlic, and cocoa.
Salt –Excess intake disrupts Lactobacillus populations, reduces SCFAs, and drives Th17-mediated inflammation.

Beyond Diet: Additional Modulators and Microbiome-Targeted Therapies

Food additives and chemicals: Emulsifiers degrade the mucus barrier; artificial sweeteners alter microbial metabolism; herbicides such as glyphosate may disrupt microbial communities.
Probiotics and fermented foods: Selected Lactobacillus and Bifidobacterium strains have demonstrated BP-lowering effects in clinical trials.
FMT (Fecal Microbiota Transplantation): Preclinical studies confirm that microbial transfer can alter BP phenotypes, though human evidence is limited.

From Universal Guidelines to Precision Nutrition

While Mediterranean and DASH diets provide foundational frameworks, inter-individual variability in microbiome composition means that responses differ widely. Precision nutrition—tailoring dietary interventions to a patient’s microbiome, genetics, and clinical phenotype—represents the future of hypertension management. Advances in microbiome sequencing, metabolomics, and biomarker discovery will enable predictive models for patient-specific dietary guidance.

Discussion and Future Perspectives

The convergence of microbiome science and nutrition offers a transformative opportunity in hypertension therapy. Priorities for future research include:

Conducting large-scale human trials of microbiome-directed dietary and probiotic interventions.
Developing microbiome-based biomarkers for hypertension risk stratification.
Elucidating molecular pathways linking microbial metabolites to host organ systems.
Integrating microbiome assessment into clinical guidelines and primary care.

Conclusion

Hypertension management is shifting from a pharmacocentric model to a systems-based, holobiont-informed paradigm. By targeting the gut–kidney–brain axis through diet and microbiome-based therapeutics, we can advance beyond symptom control toward disease modification. Precision nutrition and microbial therapeutics represent not only adjuncts but essential components of next-generation cardiovascular care.