Intestinal Serotonergic Vagal Signaling as a Mediator of Microbiota-Induced Hypertension

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.