Intestinal Serotonergic Vagal Signaling as a Mediator of Microbiota-Induced Hypertension
12 affiliations
- 1Monell Chemical Senses Center, University of Pennsylvania, Philadelphia (A.d.A., A.S., G.d.L.).
- 2Department of Neurosurgery, Brain and Spine, University of South Florida, Tampa (H.S.K., E.B.O., A.A.P., J.Z.).
- 3Microbiomes Institute, University of South Florida, Tampa (H.S.K., E.B.O., A.A.P., J.Z.).
- 4Department of Neurosciences, University of Toledo, OH (H.S.K., N.R.B.).
- 5Department of Physiology and Pharmacology, University of Toledo, OH (T.Y., E.W.D., D.S.M.).
- 6Department of Neuroscience, University of Florida, Gainesville (D.M.B.).
- 7Department of Cell and Cancer Biology, University of Toledo, OH (M.R.D., I.d.l.S.).
- 8Department of Oral and Maxillofacial Surgery, University of Florida, Gainesville (B.D.A.).
- 9Department of Surgery, University of Toledo, OH (A.L.K.).
- 10Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville (T.J.G.).
- 11Tampa General Hospital Precision Medicine Biorepository, University of South Florida (B.S., M.L.A.).
- 12Department of Physiological Sciences, University of Florida, Gainesville (C.J.M.).
Abstract
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.
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BibTeX
@article{araujo2026intestinal,
title = {{Intestinal Serotonergic Vagal Signaling as a Mediator of Microbiota-Induced Hypertension}},
author = {Alan de Araujo and Hemaa Sree Kumar and Tao Yang and Emily B. Otmanowski and Adriana Alviter Plata and Elliott W. Dirr and Nicole R. Bearss and David M. Baekey and Megan R. Dreier and Ivana de la Serna and Darren S. Miller and Basak Donertas-Ayaz and Arashdeep Singh and Andrea L. Kalinoski and Timothy J. Garrett and Brittney Short and Matthew L. Anderson and Christopher J. Martyniuk and Guillaume de Lartigue and Jasenka Zubcevic},
journal = {Circulation},
year = {2026},
month = sep,
doi = {10.1161/circulationaha.124.072363},
url = {https://doi.org/10.1161/circulationaha.124.072363},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Intestinal Serotonergic Vagal Signaling as a Mediator of Microbiota-Induced Hypertension
AU - Alan de Araujo
AU - Hemaa Sree Kumar
AU - Tao Yang
AU - Emily B. Otmanowski
AU - Adriana Alviter Plata
AU - Elliott W. Dirr
AU - Nicole R. Bearss
AU - David M. Baekey
AU - Megan R. Dreier
AU - Ivana de la Serna
AU - Darren S. Miller
AU - Basak Donertas-Ayaz
AU - Arashdeep Singh
AU - Andrea L. Kalinoski
AU - Timothy J. Garrett
AU - Brittney Short
AU - Matthew L. Anderson
AU - Christopher J. Martyniuk
AU - Guillaume de Lartigue
AU - Jasenka Zubcevic
PY - 2026
DA - 2026/09/15
JO - Circulation
DO - 10.1161/circulationaha.124.072363
UR - https://doi.org/10.1161/circulationaha.124.072363
AB - 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.
SN - 0009-7322
SN - 1524-4539
ER -