Hypertension

SCFA-Mediated BP Regulation#

SCFAs regulate blood pressure through opposing receptor systems. GPR41 (FFAR3): Propionate and Butyrate binding causes vasodilation and BP reduction via endothelial relaxation. Olfr78 (olfactory receptor 78, renal): Propionate and acetate binding on renal juxtaglomerular cells stimulates renin release, raising BP.

At physiological SCFA concentrations, the vasodilatory GPR41 effect dominates, producing net BP reduction.^{[1]Emerging therapy targets to modulate microbiome-mediated effects evident in cardiovascular diseaseDorothea Katharina Hoffelner, Tim Hendrikx · 2025Open reference 1 ↓} Dysbiosis-driven SCFA depletion removes this vasodilatory brake, contributing to hypertension. High-fiber diets increase colonic SCFA production and are consistently associated with lower BP.

TMAO and Vascular Remodeling#

Prolonged Trimethylamine N-Oxide (TMAO) elevation activates pro-inflammatory vascular remodeling pathways, contributing to arterial stiffness and increased peripheral resistance.^{[2]The gut microbial metabolite trimethylamine N-oxide and cardiovascular diseasesJing Zhen, Zhou Zhou, Meng He et al. · 2023Open reference 2 ↓} TMAO-associated Firmicutes/Bacteroidetes ratio elevation is characteristic of hypertensive microbiomes. TMAO promotes endothelial dysfunction via HMGB1/TLR4 signaling and tight junction destruction.

Bile Acid-FXR Axis#

FXR agonist CDCA reduces blood pressure in spontaneously hypertensive rat models through iNOS expression.^{[3]Bile acids at the cross-roads of gut microbiome-host cardiometabolic interactionsPaul M. Ryan, Catherine Stanton, Noel M. Caplice · 2017Open reference 3 ↓} FXR expression is downregulated in left ventricle of hypertensive rats with end-stage heart failure. Bile Acid Metabolism disruption may compound SCFA depletion in raising BP.

Malassezia Enrichment#

Malassezia increases progressively from normotensive to pre-hypertensive to hypertensive individuals (28.45% dominance in HTN vs lower in NT).^{[4]Gut mycobiome dysbiosis contributes to the development of hypertension and its response to immunoglobulin light chainsYeqing Zou, Anxing Ge, Brako Lydia et al. · 2022Open reference 4 ↓}

Malassezia produces inflammatory lipases and activates immune cells; its enrichment compounds bacterial dysbiosis-driven Metal-Driven Inflammation. Malassezia positively associated with immunoglobulin light chain kappa in pre-HTN (r=0.510, P=0.044) and both kappa and lambda in HTN.

HTN+CKD Comorbidity#

HTN+CKD patients show the most severe mycobiome disruption: Malassezia (18.71%) dominant, with increased Apiotrichum, Cystobasidium, Saccharomyces, and decreased Candida, Meyerozyma.^{[5]Exploring the gut mycobiome: differential composition and clinical associations in hypertension, chronic kidney disease, and their comorbidityJuan Qiu, Longyou Zhao, Yiwen Cheng et al. · 2023Open reference 5 ↓}

HTN+CKD has higher IL2Ralpha, IL18, TNF-alpha; Candida negatively associated with TNF-alpha. Fungal dysbiosis occurs at the pre-hypertension stage, suggesting it precedes clinical disease.

FMT for Hypertension: First Human RCT#

Fan et al. 2025 conducted the first multicenter, randomized, blinded, placebo-controlled trial of oral FMT for stage 1 hypertension (NCT04406129).^{[6]Fecal microbiota transplantation for hypertension: an exploratory, multicenter, randomized, blinded, placebo-controlled trialLuyun Fan, Junru Chen, Qi Zhang et al. · 2025Open reference 6 ↓}

124 patients (mean age 43), 7 centers in China. Primary outcome: SBP change at day 30 was -6.28 mmHg (FMT) vs -5.77 mmHg (placebo), p=0.62 (not significant). Transient effect: At 1 week, FMT produced -4.34 mmHg between-arm SBP difference (p=0.024), but this did not persist.

Age subgroup: Participants >48 years showed significant SBP reduction of 7.65 mmHg (p=0.029). Microbial shifts: Increased Parabacteroides merdae, Prevotella copri, Eubacterium sp.; decreased Eggerthella lenta, Streptococcus vestibularis. Metabolite associations: SBP-associated metabolites included tyrosine, glutamine, phenylalanine, methionine.

Implication: microbial BP modulation is real but transient, suggesting repeated or sustained intervention is needed.

Lead#

lead (Pb) is among the most established environmental risk factors for hypertension. Mechanisms: inhibits endothelial NO synthase, increases Oxidative Stress, activates RAAS (renin-angiotensin-aldosterone system), promotes vascular smooth muscle contraction. Even low-level chronic lead exposure (blood lead <10 ug/dL) is associated with elevated BP.

lead accumulates in kidney, impairing renal BP regulation.

Cadmium#

cadmium (Cd) nephrotoxicity damages renal tubules, impairing sodium handling and BP regulation. cadmium-induced oxidative stress in vascular endothelium promotes arterial stiffness. cadmium accumulates in renal cortex over decades; renal cadmium burden correlates with hypertension risk.

Renal Metal Accumulation#

The kidney is a primary target organ for both lead (Pb) and cadmium (Cd) accumulation. Metal-induced renal damage impairs the kidney's central role in long-term BP regulation (sodium excretion, RAAS modulation, prostaglandin synthesis). This creates a direct metal-to-hypertension pathway independent of the microbiome, though both pathways likely operate simultaneously.