Interaction of the Vagus Nerve and Serotonin in the Gut-Brain Axis

Abstract

The gut-brain axis represents an important bidirectional communication network, with the vagus nerve acting as a central conduit for peripheral signals from the various gut organs to the central nervous system. Among the molecular mediators involved, serotonin (5-HT), synthesized predominantly by enterochromaffin cells in the gut, plays a pivotal role. Gut-derived serotonin activates vagal afferent fibers, transmitting signals to the nucleus tractus solitarius (NTS) and modulating serotonergic neurons in the dorsal raphe nucleus (DRN) as well as the norepinephrinergic neurons in the locus coeruleus (LC). This interaction influences emotional regulation, stress responses, and immune modulation. Emerging evidence also highlights the role of microbial metabolites, particularly short-chain fatty acids (SCFAs), in enhancing serotonin synthesis and vagal activity, thereby shaping gut-brain communication. This review synthesizes the current knowledge on serotonin signaling, vagal nerve pathways, and central autonomic regulation, with an emphasis on their implications for neuropsychiatric and gastrointestinal disorders. By elucidating these pathways, novel therapeutic strategies targeting the gut-brain axis may be developed to improve mental and physical health outcomes.

Keywords: dorsal raphe nucleus; gut–brain axis; locus coeruleus; nucleus tractus solitaries; serotonin; short-chain fatty acids; vagus nerve.

Figure 1

Serotonin-mediated communication within the gut–brain axis via the vagus nerve. This figure illustrates the bidirectional interactions between the gut and brain, emphasizing the role of serotonin (5-HT) and the vagus nerve. In the gut, tryptophan, derived from dietary sources, is converted into serotonin through the action of tryptophan hydroxylase (TPH1) and aromatic L-amino acid decarboxylase (AADC). The gut microbiome influences serotonin production by releasing short-chain fatty acids (SCFAs), which modulate TPH1 expression and serotonin synthesis. Serotonin produced in the gut activates vagal afferent fibers, which transmit signals to the nucleus tractus solitarius (NTS) in the brainstem. The NTS integrates serotonergic signals and projects to higher-order brain regions involved in autonomic regulation, mood, and immune function. Key brainstem nuclei, including the dorsal motor vagal nucleus, participate in efferent signaling back to the gut, completing the feedback loop. This dynamic system highlights the essential role of serotonin in gut-brain communication and the influence of gut microbiota in regulating neural and physiological responses.

Figure 2

Serotonin and norepinephrine pathways connecting the gut and brain through the vagus nerve. This diagram highlights the dual involvement of serotonin (blue pathways) and norepinephrine (red pathways) in gut–brain communication via the vagus nerve. Serotonin produced in the gut interacts with 5-HT3 receptors located on vagal afferent fibers, transmitting signals to the nucleus of the solitary tract in the brainstem. The nucleus tractus solitarius (NTS) integrates these serotonergic signals and projects them to higher brain regions, including the dorsal raphe nucleus, locus coeruleus, hippocampus, and cortex, where they influence mood, cognition, and stress responses. In parallel, norepinephrine pathways originating from the LC modulate various cortical and subcortical regions, playing a key role in arousal, attention, and immune regulation. The interplay between these neurotransmitter systems is essential for maintaining homeostasis, as serotonin influences norepinephrine release and vice versa, creating a feedback loop that supports adaptive responses to internal and external stimuli.