# Gut Microbiota as an Endocrine Organ: Unveiling Its Role in Human Physiology and Health
## 3 Neurohormones and Their Role in Microbial Effects  
### The Gut-Brain Axis and Hormonal Mediation  
The intricate interaction between the brain and gut microbiota, often termed the 'gut-brain axis', is primarily mediated by the extensive network of the vagus nerve. While the precise pathways of this axis remain incompletely understood, hormonal mediation plays a crucial role [28]. The microbiota's influence on host hormone levels can occur directly, with the microbiota producing hormones, or indirectly, impacting the adrenal cortex, inflammation, and immune responses. Critical hormones in bacterial effects on host behaviour include neurohormones (e.g., serotonin and catecholamines) and stress hormones (e.g., cortisol and corticosterone). Outside the gut, the microbiota plays a substantial role in fostering bidirectional communication between the gut and the brain [29]. Imbalances in the standard gut microbiota are associated with various pathological conditions, including neurological disorders such as Parkinson's disease, attention deficit hyperactivity disorder (ADHD), depression, anxiety, and autism [30]. Intestinal microbes play a role in neurotransmitter synthesis, influencing both the central nervous system (CNS) and the periphery [31; 32]. Changes in neurotransmitters, including glutamate, serotonin, noradrenaline, dopamine, and \(\gamma\)-aminobutyric acid (GABA), activate nerve ganglia in the enteric nervous system (ENS). Multiple mechanisms facilitate the gut-brain axis, such as the activation of vagal afferents by glutamate and serotonin. These pathways transmit signals through the vagus nerve from the gut lumen to the central nervous system (CNS) [33]. Microbes can interact directly with the CNS through serotonin secretion into the lamina propria or translocation of metabolites and endotoxins from the intestinal lumen to the central circulation [13]. Vagal afferents, activated by signals such as hormones, nutrients, and peptides produced by intestinal microbes, play a crucial role in modulating afferent vagal nerve activity. SCFA-producing microbes directly act on intestinal vagal terminals, influencing vagal afferent firing frequency. Specific microbes alter brain neurochemistry and behaviour relevant to the dopaminergic system, with the vagus nerve serving as a primary mediator in the gut-brain crosstalk, influencing central and peripheral dopamine concentrations [34]. In addition to SCFAS, gut microbes facilitate bidirectional communication with the CNS, the immune system, and the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis, known for its dynamic role in the stress response and gut-brain communication, is vital in maintaining homeostasis. Studies from germ-free (GF) rodents indicate that the absence of gut microbiota is associated with a hyperreactive HPA axis in response to stress [22]. Colonisation of faecal matter with the normal flora of healthy rodents partially normalises this hyperreactivity, emphasising the importance of microbiota in HPA axis homeostasis. Moreover, intestinal microbes normalise the stress response by affecting HPA axis gene expression during chronic stress. For instance, gut microbiota downregulates the FK506-binding protein 5 (Fkbp5) gene, regulating the negative feedback loop and reducing cortisol affinity for glucocorticoid receptors [35]. In the absence of gut microbiota, dysregulation of negative feedback leads to an exaggerated HPA response. While regulated by gut microbiota, stress-inducing events can contribute to detrimental effects on the normal intestinal flora. Hyperactivation of the HPA axis leads to gut microbiota dysbiosis by producing proinflammatory cytokines (e.g., IL-18, IL-6, and TNF) [36]. This dysbiosis can result in neurotransmitter dysregulations, influencing unfavourable behaviours via gut-brain crosstalk. However, administering beneficial gut microbes, such as Lactobacillus plantarum PS128, to GF mice has demonstrated significant increases in dopamine levels and improvements in anxiety-like behaviours [37].