The neurotransmitter and hormonal molecule 5-hydroxytryptamine (5-HT), commonly known as serotonin, represents a critical biochemical compound extensively distributed throughout neurological and peripheral biological systems. Its multifaceted physiological significance encompasses a broad spectrum of regulatory functions, including modulation of emotional states, cognitive processes, motivational mechanisms, learning capabilities, mnemonic functions, thermoregulation, circadian rhythms, reproductive behaviors, and metabolic appetite control.
The intricate biochemical landscape of serotonergic metabolism extends beyond conventional understanding, characterized by sophisticated synthesis and degradation pathways. Moreover, emerging research illuminates the complex interactions between host biochemical systems and microbial populations, revealing nuanced interdependencies that profoundly influence physiological and pathological mechanisms.
Contemporary scientific investigations have increasingly focused on elucidating the intricate relationships between host biochemistry and microbial dynamics, progressively unveiling serotonin's sophisticated metabolic processes. This review will systematically examine the fundamental mechanisms underlying serotonin metabolism, explore the synergistic interactions between host systems and microorganisms, and analyze its consequential impacts across physiological and pathological domains.
Synthesis And Metabolism Of Serotonin
Tryptophan As A Precursor For Serotonin Synthesis
The production of serotonin originates from tryptophan (Trp), an indispensable amino acid primarily obtained from dietary sources. Tryptophan undergoes metabolism in the body via three principal routes: the kynurenine pathway (KP), the indole pathway, and the serotonin biosynthesis pathway. This metabolic process not only yields a range of significant byproducts but also dynamically adjusts to varying environmental and physiological states by modulating tryptophan concentrations within the body.
Serotonin biosynthesis occurs in two critical stages. Initially, tryptophan is converted into 5-hydroxytryptophan (5-HTP) through hydroxylation, catalyzed by the enzyme tryptophan hydroxylase (TPH). TPH acts as the rate-limiting enzyme in serotonin production, with its activity directly influencing the speed of serotonin synthesis. Subsequently, 5-HTP is transformed into 5-hydroxytryptamine (5-HT) via decarboxylation, a reaction facilitated by aromatic L-amino acid decarboxylase (AADC).
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Serotonin Metabolic Pathway
The metabolism of serotonin is mainly carried out by enzymes such as monoamine oxidase (MAO) and indoleamine 2,3-dioxygenase (IDO). MAO is responsible for degrading serotonin into 5-hydroxyindoleacetic acid (5-HIAA), while IDO converts tryptophan into kynurenine (Kyn). The metabolites of serotonin not only play a role in physiological processes, but also affect the overall health of the host by regulating the metabolic balance of tryptophan.
Figure 1. Serotonin metabolism pathways.
Degradation Of Serotonin
After serotonin exerts its physiological effects, most of it will be reabsorbed back into the presynaptic neuron by the serotonin transporter (SERT) on the presynaptic membrane. Part of the reabsorbed serotonin will be repackaged into synaptic vesicles for reuse, while the other part will be degraded and metabolized by enzymes such as MAO and eventually excreted from the body. SERT activity is essential for maintaining serotonin homeostasis, and its dysfunction is associated with a variety of mental illnesses.
Host And Microbial Serotonin Metabolism
Host-Microbe Interactions In Serotonin Metabolism
The relationship between the microbiota and the host significantly influences serotonin metabolism. Through various mechanisms, such as the direct production of serotonin, modulation of tryptophan accessibility, and impact on the host's metabolic processes, the gut microbiota regulates serotonin levels in the host. Research has demonstrated that germ-free (GF) mice exhibit elevated circulating tryptophan levels and reduced serotonin levels, highlighting the critical role of gut microbiota in the metabolic regulation of serotonin within the host.
Figure 2. Serotonin at the host/microbial interface. (Nunzi, E., et al., 2025)
Regulation Of Host Serotonin Levels By The Gut Microbiota
The gut microbiota regulates host serotonin levels through multiple pathways. Some microorganisms are able to express tryptophan synthase, which directly synthesizes serotonin. In addition, microbial metabolites such as short-chain fatty acids (SCFAs), indoles, and lipopolysaccharides (LPS) can also indirectly affect serotonin levels by regulating host metabolic pathways. For example, some gut microorganisms can absorb serotonin, while others, such as Akkermansia muciniphila, increase serotonin levels in the colon and hippocampus by reducing the expression of MAO and increasing the expression of TPH.
Serotonin's Opposing Effects On The Gut Microbiota
Serotonin not only affects the physiological functions of the host, but also regulates the composition and function of the intestinal microbiota through a variety of mechanisms. Studies have shown that serotonin can affect the growth, quorum sensing and virulence of intestinal bacteria. For example, serotonin can regulate microbial signal transduction and adaptability by activating microbial receptors such as membrane-bound histidine kinase CpxA. This bidirectional regulatory mechanism not only maintains the homeostasis between the host and the microorganisms, but also has an important impact on overall health.
Bidirectional Signaling Between Host And Microbes Via Serotonin
Serotonin plays a key role in bidirectional signaling between the host and microbes. Intestinal microbes regulate the host's serotonin synthesis and metabolism by producing metabolites and signaling molecules. In turn, serotonin produced by the host can also affect the growth and function of microbes. This bidirectional signaling not only regulates the physiological function of the host, but also affects the composition and diversity of the microbiota. For example, serotonin can affect the survival and adaptability of microbes by regulating the pH and redox state of the intestinal environment.
Role of Serotonin in Host Physiology
Functions of Serotonin in The Central Nervous System
Serotonin plays a variety of important functions in the central nervous system, including regulating mood, sleep, cognition and behavior. Serotonergic neurons are mainly concentrated in the raphe nuclei of the brainstem. These neurons project widely to various areas of the brain and participate in regulating mood, anxiety, depression and cognitive function. For example, serotonin produces an anti-anxiety effect by activating the 5-HT1A receptor; and affects the pathological mechanism of mental illnesses such as schizophrenia by activating the 5-HT2A receptor.
Figure 2. Central serotonergic pathways, effects, and drugs. (Berger, M., et al., 2009)
Role of Serotonin in The Gastrointestinal Tract
Serotonin acts as a paracrine factor in the gastrointestinal tract, regulating intestinal motility, appetite, and digestive function. About 90% of serotonin is synthesized by enterochromaffin cells (EC) in the intestinal mucosal layer. When food enters the intestine, EC cells release serotonin, which acts on 5-HT3 and 5-HT4 receptors on intestinal smooth muscle cells, causing intestinal motility. In addition, serotonin can transmit signals to the central nervous system through pathways such as the vagus nerve, forming a two-way communication of the brain-gut axis, affecting emotions and satiety.
The Role of Serotonin in The Cardiovascular System
Serotonin regulates the contraction and relaxation of blood vessels through its receptors in the cardiovascular system and participates in blood pressure regulation and thrombosis. Serotonin can be absorbed by platelets and released when needed to help repair wounds by narrowing blood vessels, slowing blood flow and promoting clot formation. In addition, serotonin is also related to the development of atherosclerosis, and its metabolites may participate in oxidative stress reactions and promote the process of atherosclerosis.
Interactions Between Serotonin And The Endocrine System
Serotonin is a precursor to melatonin and affects the sleep-wake cycle by regulating the synthesis and release of melatonin. In addition, serotonin is also related to growth hormone (GH) and dehydroepiandrosterone (DHEA) levels. Lower serotonin levels are associated with aging, lower growth hormone, and lower dehydroepiandrosterone sulfate (DHEAS) levels. Serotonin plays an important role in maintaining the balance of the endocrine system.
The Relationship Between Serotonin And Disease
Serotonin Deficiency and Mood Disorders
Low serotonin levels are closely tied to several mood-related conditions, such as depression, anxiety, and mania. Individuals with these disorders frequently exhibit irregularities in serotonin levels, which disrupt normal mood regulation. Medications like selective serotonin reuptake inhibitors (SSRIs) work by blocking SERT, enhancing serotonin availability in the synaptic cleft, and subsequently improving mood and cognitive performance.
Serotonin and Neurodegenerative Diseases
Disruptions in serotonin metabolism are implicated in neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Affected individuals often experience a decline in serotonergic neurons and diminished serotonin levels, contributing to cognitive impairments and emotional disturbances.
Disease Serotonin and Cardiovascular Disease
The involvement of serotonin in cardiovascular diseases is increasingly recognized. Research indicates that serotonin influences vascular tone by interacting with its receptors, playing a role in blood pressure control and thrombus formation. Furthermore, serotonin is associated with the pathogenesis of atherosclerosis, as its byproducts may contribute to oxidative stress, accelerating the disease's progression.
Serotonin and Osteoporosis
Serotonin is critical in maintaining bone density, with elevated levels potentially leading to bone weakening or osteoporosis. Evidence suggests that serotonin modulates bone metabolism by affecting the balance between osteoblast and osteoclast activity. Consequently, managing serotonin levels could be a key strategy in the prevention and treatment of osteoporosis.
Clinical Interventions in Serotonin Metabolism
Antidepressant Medications
Serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used antidepressants. These drugs inhibit SERT and increase the concentration of serotonin in the synaptic cleft, thereby improving mood and cognitive function. In addition, drugs targeting serotonin receptors are also being developed in order to provide more precise treatment options.
Non-pharmacological Interventions
Non-drug interventions such as cognitive behavioral therapy (CBT), transcranial magnetic stimulation (rTMS), and lifestyle modifications have also been used to regulate serotonin levels and improve symptoms in patients with mental illness. Studies have shown that these non-drug interventions can improve mood and cognitive function by regulating neurotransmitter systems.
Microbial Intervention
The use of probiotics and prebiotics has shown potential in regulating serotonin metabolism. Studies have shown that certain probiotics can increase serotonin synthesis by regulating the composition and function of the intestinal microbiota. In addition, prebiotics such as inulin and oligofructose can also indirectly increase serotonin levels by promoting the growth of beneficial microorganisms. Therefore, microbial intervention may become a new strategy for the treatment of mental illness in the future.
Conclusion
Serotonin metabolism plays a central role in host health, and its regulation involves the synergistic interaction between the host and the microbe. A deeper understanding of the mechanisms of serotonin metabolism and the host-microbe interaction could provide new strategies for the treatment of a variety of diseases. Future research should focus on further revealing these mechanisms and developing personalized treatment regimens and precision medicine strategies to enhance treatment outcomes and improve patients' quality of life.
References
- Nunzi, E., Parano, M., Costantini, C., Garaci, E., Puccetti, P., & Romani, L. (2025). Host-microbe serotonin metabolism. Trends in endocrinology and metabolism: TEM, 36(1), 83–95. https://doi.org/10.1016/j.tem.2024.07.014
- Berger, M., Gray, JA, & Roth, BL (2009). The expanded biology of serotonin. Annual review of medicine, 60, 355–366. https://doi.org/10.1146/annurev.med.60.042307.110802
