Lighting Up the Gut–Brain Axis: Akkermansia Triggers Vagal Serotonergic Signaling

Gut dysbiosis is implicated in multiple cardiometabolic conditions, including hypertension, yet the specific host-microbiota mechanisms driving these effects remain poorly defined. Using fecal microbiota transplantation (FMT) from spontaneously hypertensive rats (SHR) into normotensive Wistar-Kyoto (WKY) controls, we identified loss of Akkermansia muciniphila as a candidate microbial driver of dysbiosis-associated hypertension. In rodents, reduced A. muciniphila abundance was correlated with elevated blood pressure, diminished colonic serotonin (5-HT) availability, and impaired 5-HT3a receptor-dependent vagal signaling along the vagal gut–brain axis. In a cohort of hypertensive middle-to-older adults, A. muciniphila levels were similarly reduced (~5-fold, p< 0.05), accompanied by lower serotonin levels and decreased 5-HT3a receptor expression in colonic biopsies (p< 0.01), supporting translational relevance. Conversely, treatment of primary colonic epithelial cells with A. muciniphila enriched media elevated serotonin release in vitro (~20-fold, p< 0.0001), while daily oral supplementation of A. muciniphila (10 8 CFU for 8 weeks) alleviated age-dependent hypertension in the SHR and restored both colonic serotonin and vagal 5-HT3a receptor expression, suggesting a microbial effect on the serotonergic vagal gut-brain axis. To test this, we generated a novel transgenic zebrafish line, Tg(5ht3a-GCaMP), via a c-terminal fusion of Cre to the endogenous 5ht3a gene and a cre-responsive GCaMP reporter. Anatomical and functional validation using fluorescence imaging confirmed receptor-specific activation: larval vagal sensory ganglia exhibited robust GCaMP responses following exposure to the 5-HT3 agonist 1-phenylbiguanide, which were abolished by the antagonist ondansetron. Remarkably, immersing live anesthetized larvae in A. muciniphila–enriched media significantly increased vagal ganglia cell activation (~7-fold, p< 0.01), an effect fully blocked by ondansetron pre-treatment. Together, these findings identify A. muciniphila as a microbial regulator of blood pressure acting through serotonin-dependent vagal gut-brain pathways. We introduce an innovative zebrafish model for real-time imaging of microbe-to-vagus communication that can provide a mechanistic insight into the gut-brain axis and highlight potential therapeutic strategies targeting microbial regulation of autonomic function. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.