Jasenka Zubcevic

BACKGROUND: Hypertension is a pervasive global health challenge, impacting more than 1 billion individuals worldwide. Despite strides in therapeutic strategies, a significant proportion of patients remain resistant to the currently available therapies. Although conventional treatments predominantly focus on cardiac, renal, and cerebral targets, emerging research underscores the pivotal role of the gut and its microbiota. Yet, the precise mechanisms governing interactions between the gut microbiota and the host blood pressure remain unclear. METHODS: We combined fecal microbiota transplantation between normotensive and hypertensive rats, an intersectional genetic strategy in a serotonin receptor 3a (5HT3a) receptor Cre rat line to activate, ablate, and restore serotonin-sensing colonic vagal neurons, in vivo calcium imaging and radiotelemetric blood pressure recordings, and measurements of intestinal serotonin (5-hydroxytryptamine [5-HT]) and 5HT3a receptor signaling in rats and in colonic biopsies from normotensive and hypertensive human subjects (N=5 per group; 36 to 75 years of age). RESULTS: A marked decrease in both intestinal 5-HT and vagal 5HT3a receptor signaling was observed in hypertensive rats and humans, and in rats subjected to fecal microbiota transplantation from hypertensive rats. Leveraging the intersectional genetic strategy in a Cre rat line, we demonstrate that intestinal 5HT3a receptor vagal signaling is a crucial link between the gut microbiota and blood pressure homeostasis and that recovery of 5-HT signaling in colon-innervating vagal neurons can alleviate hypertension. CONCLUSIONS: Here, we describe a neural host-microbiota interaction that is mediated by intestinal serotonin (5-HT) signaling via the vagal 5HT3a, which is crucial for maintenance of blood pressure homeostasis. This finding enhances our comprehension of hypertensive pathophysiology and unveils a promising new therapeutic target for combating resistant hypertension associated with gut dysbiosis.

We present a compartmentalized microfluidic trichannel model of the gut-brain axis that reveals how microbial metabolites communicate with neurons. Using this model, we show that butyrate triggers colonic serotonin release, which activates neuronal signaling through calcium influx. This work highlights the power of microfluidic models to uncover mechanisms of gut-brain communication in a controlled, in vitro setting.

Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved signaling molecule present across diverse taxa, including plants, invertebrates, and vertebrates. In mammals, the majority of peripheral serotonin is synthesized in the gastrointestinal tract by enteric neurons and enterochromaffin cells via tryptophan hydroxylases. Its biosynthesis and release are influenced by dietary components and microbial metabolites, particularly short-chain fatty acids produced by the gut microbiota. Once released into the periphery, serotonin exerts pleiotropic effects, regulating intestinal motility and secretion, modulating vascular tone, and influencing blood pressure through both direct actions and vagal sensory pathways engaging central and autonomic circuits. Dysregulation of colonic serotonin production or signaling has been implicated in metabolic, neuropsychiatric, and cardiovascular disorders, including postprandial blood pressure abnormalities and hypertension. Emerging evidence highlights a bidirectional relationship between gut microbes and host serotonergic pathways, suggesting that microbiota-targeted interventions may hold therapeutic potential for cardiometabolic regulation. Advancing our understanding of gut serotonergic signaling, particularly the interplay between host and microbial factors, could inform the development of innovative strategies to treat hypertension and related conditions.

Salt-sensitive and salt-induced hypertension (SHTN) is a multifaceted and heterogeneous condition influenced by various factors, including lifestyle, genetics, sex, age, and dietary salt intake. Despite its prevalence, affecting about 50% of hypertensive and 25% of normotensive individuals, the precise mechanisms driving salt sensitivity remain incompletely understood. The central nervous system (CNS) plays a pivotal role in SHTN, as it detects changes in plasma and cerebrospinal fluid sodium (Na⁺) concentrations and integrates sensory signals from peripheral organs. These inputs, in turn, regulate the autonomic nervous system, leading to an increase in sympathetic nerve activity that contributes to the onset of SHTN. This review examines the CNS mechanisms involved in SHTN, focusing on the key afferent and efferent pathways in its pathogenesis. We summarize recent findings on critical neural circuits activated by dietary salt and examine several key signaling pathways, including the brain’s renin-angiotensin system, aldosterone-“ouabain,” and salt-sensitive G proteins. Additionally, we discuss the clinical relevance of targeting the CNS for SHTN treatment and review current therapeutic approaches.

Background: The global rise in the prevalence and incidence of cardiometabolic disorders – such as obesity, hypertension, and insulin resistance – has reached alarming levels and poses a significant public health concern. Dietary patterns characterized by excessive consumption of sodium, refined carbohydrates, and unhealthy fats are primary contributors to this trend. Emerging evidence suggests that dietary interventions can improve metabolic health, in part by modulating gut microbiota. Objective:This review aims to synthesize current understanding of diet–microbiota–host interactions and identify key areas for developing sustainable, physiology-based interventions for cardiometabolic disease management. Methods:For this narrative review, a comprehensive literature search was conducted across major biomedical sciences databases, including PubMed and Web of Science, supplemented by Google Scholar. Literature published up to June of 2025 was included, with emphasis on most recent findings and supported by seminal works. Studies were evaluated for relevance and methodological rigor. Results:Current evidence supports a triadic relationship among diet, gut dysbiosis, and cardiometabolic dysfunction, underscoring the complex interplay between nutrition and host physiology. The Western diet, high in sodium and carbohydrates, can disrupt gut microbial communities, thereby altering intestinal nutrient absorption leading to an increased incidence of cardiometabolic diseases. Targeted manipulation of the gut microbiota, through probiotics or other modulators, may offer novel avenues to regulate metabolism and maintain nutrient homeostasis. Conclusion:The integration of nutritional, microbial, and physiological perspectives offers a promising framework for cardiometabolic disease prevention and treatment. To move beyond associative findings, future research should prioritize mechanistic studies to clarify the pathways by which gut microbiota influence host nutrient and micronutrient handling. This will be critical to unlocking the therapeutic potential of both dietary modulation and microbiota-targeted strategies in maintaining homeostasis.

An over-active renin-angiotensin system (RAS) is characterized by elevated angiotensin II (Ang II). While Ang II can promote metabolic and mitochondrial dysfunction in tissues, little is known about its role in the gastrointestinal system (GI). Here, we treated rat primary colonic epithelial cells with Ang II (1–5000 nM) to better define their role in the GI. We hypothesized that Ang II would negatively affect mitochondrial bioenergetics as these organelles express Ang II receptors. Ang II increased cellular ATP production but reduced the mitochondrial membrane potential (MMP) of colonocytes. However, cells maintained mitochondrial oxidative phosphorylation and glycolysis with treatment, reflecting metabolic compensation with impaired MMP. To determine whether lipid dysregulation was evident, untargeted lipidomics were conducted. A total of 1949 lipids were detected in colonocytes spanning 55 distinct (sub)classes. Ang II (1 nM) altered the abundance of some sphingosines [So(d16:1)], ceramides [Cer-AP(t18:0/24:0)], and phosphatidylcholines [OxPC(16:0_20:5(2O)], while 100 nM Ang II altered some triglycerides and phosphatidylserines [PS(19:0_22:1). Ang II did not alter the relative expression of several enzymes in lipid metabolism; however, the expression of pyruvate dehydrogenase kinase 2 (PDK2) was increased, and PDK2 can be protective against dyslipidemia. This study is the first to investigate the role of Ang II in colonic epithelial cell metabolism.

An over-active renin-angiotensin system (RAS) is characterized by elevated angiotensin II (Ang II). While Ang II can promote metabolic and mitochondrial dysfunction in tissues, little is known about its role in the gastrointestinal system (GI). Here, we treated rat primary colonic epithelial cells to Ang II (1-5000 nM) to better define its role in the GI. We hypothesized that Ang II would negatively affect mitochondrial bioenergetics as these organelles express Ang II receptors. Ang II increased cellular ATP production but reduced mitochondrial membrane potential (MMP) of colonocytes. However, cells maintained mitochondrial oxidative phosphorylation and glycolysis with treatment, reflecting metabolic compensation with impaired MMP. To determine whether lipid dysregulation was evident, untargeted lipidomics were conducted. 1949 lipids were detected in colonocytes spanning 55 distinct (sub)classes. Ang II (1 nM) altered the abundance of some sphingosines [So(d16:1)], ceramides [Cer-AP(t18:0/24:0)], and phosphatidylcholines [OxPC(16:0_20:5(2O)], while 100 nM Ang II altered some triglycerides and phosphatidylserines [PS(19:0_22:1). Ang II did not alter the relative expression of several enzymes in lipid metabolism; however, expression of pyruvate dehydrogenase kinase 2 (PDK2) was increased and PDK2 can be protective against dyslipidemia. This study is the first to investigate the role of Ang II on colonic epithelial cell metabolism.

Hypertension is a pervasive global health challenge, impacting over a billion individuals worldwide. Despite strides in therapeutic strategies, a significant proportion of patients remain resistant to the currently available therapies. While conventional treatments predominantly focus on cardiac, renal, and cerebral targets, emerging research underscores the pivotal role of the gut and its microbiota. Yet, the precise mechanisms governing interactions between the gut microbiota and the host blood pressure remain unclear. Here we describe a neural host-microbiota interaction that is mediated by the intestinal serotonin (5-HT) signaling via vagal 5HT3a receptors and which is crucial for maintenance of blood pressure homeostasis. Notably, a marked decrease in both intestinal 5-HT and vagal 5HT3aR signaling is observed in hypertensive rats, and in rats subjected to fecal microbiota transplantation from hypertensive rats. Leveraging an intersectional genetic strategy in a Cre rat line, we demonstrate that intestinal 5HT3aR vagal signaling is a crucial link between the gut microbiota and blood pressure homeostasis and that recovery of 5-HT signaling in colon innervating vagal neurons can alleviate hypertension. This paradigm-shifting finding enhances our comprehension of hypertensive pathophysiology and unveils a promising new therapeutic target for combating resistant hypertension associated with gut dysbiosis.

We highlight the presence of a core gut microbiota and demonstrate in vivo short-chain fatty acid production in adult zebrafish. In addition, we show cardio-beneficial vasoactive and chronotropic properties of butyrate, and chronotropic properties of acetate in anesthetized zebrafish larvae.

We show that stimulation of the ventral subdiaphragmatic vagal nerve branch may be a promising potential approach to treating hypertension. The data are especially encouraging given that rodents received only 30 min per day of intermittent stimulation therapy and in view of the potential of long-term blood pressure effects that are not stimulus-locked.