Neuroendocrine regulation of the brain-gut axis: neurotransmitters, immune communication and brain development

(2) Neuroendocrine: Microorganisms can synthesize biologically active endocrine hormones in vivo. Compared with specific pathogen-free (SPF) mice, germ-free mice secrete significantly less norepinephrine (NE) and dopamine. The catecholamines produced by the intestinal flora of SPF mice have normal biological activity, while the catecholamines in the intestinal lumen of germ-free mice exhibit a conjugated form with no biological activity. Transplanting the intestinal flora of SPF mice into germ-free mice can reverse the generation of biologically active catecholamines, confirming that the intestinal flora is crucial for the generation and activity of free catecholamines in the intestinal lumen. During gut microbiota metabolism, various neurotransmitters, cytokines, and metabolites are produced, such as serotonin (5-HT), dopamine (DA), gamma-aminobutyric acid (GABA), short-chain fatty acids (SCFA), and interleukin-1 (IL-1). These products can directly act on the enteric and vagus nerve systems, and can also influence the activity of the central nervous system through endocrine and paracrine mechanisms by regulating enteroendocrine cells. 1) The neurotransmitter 5-HT promotes adult neurogenesis, and gut bacteria play a role in 5-HTergic neural pathways in the gut and multiple brain regions. The gut microbiota can also regulate the levels of key central neurotransmitters by altering the levels of neurotransmitter precursors. 5-HT is mainly involved in the regulation of intestinal endocrine and peristalsis, as well as pain perception, and also plays an important role in the regulation of emotion and cognition. 2) Hypothalamic-Pituitary-Adrenal (HPA) Axis: Studies in animal models and humans have shown that stress is associated with increased intestinal barrier permeability, possibly mediated by hormones secreted by the hypothalamus. Biochemical changes in the brain can lead to changes in gut physiology, and the HPA axis is one of the main pathways through which these changes occur. Under environmental or psychological stress, the host HPA axis is activated, stimulating the release of various hormones that collectively affect multiple organ systems, enabling the host to adapt to the environment. 3) Immune Communication: The immune system, including adaptive and innate immunity, is an important component of the microbe-brain-gut axis. The gut itself is an important immune organ, serving as a crucial defense barrier between foreign pathogens and the internal physiological environment, and together with gut-associated lymphoid tissue, it constitutes the largest immune organ in the human body. Studies have confirmed that the immune system mediates communication between bacteria, the gastrointestinal tract, and the CNS. The CNS and peripheral immune cell pathways are considered important mechanisms by which the microbe regulates brain function and behavior. On the other hand, microorganisms and intestinal mucosal cells can also regulate the activation of immune molecules, such as pro-inflammatory factors IL-8 and IL-1, and anti-inflammatory factors IL-10 and transforming growth factor-β (TGF-β), thereby affecting the central nervous system. 4) Brain development: In recent years, many classic studies have been conducted on neurodevelopmental disorders from a genetic perspective. Gastrointestinal complications and food allergies are common in neurodevelopmental disorders, demonstrating the role of gut microbiota in neurodevelopmental diseases. Increasing evidence suggests that gut microbiota plays a significant role in the development of physical and psychological symptoms in anorexia nervosa, which has the highest mortality risk among all mental illnesses. The early stages after birth are crucial for the development of the primary and acquired immune systems. Factors such as the delivery process, neonatal care environment, inflammation, and mother-infant separation can all affect the newborn's gut microbiota, which interacts with the central nervous system through the "gut microbiota-gut-brain axis," thus influencing the development and maturation of the immune system. The gut microbiota colonizes the gastrointestinal mucosa and interacts with endocrine cells that produce more than 20 gastrointestinal hormones. These endocrine peptides act as a bridge between the gut microbiota and the host. Gastrointestinal hormone signals released under the influence of the gut microbiota are transmitted to the brain via endocrine pathways or by activating primary afferent neurons (especially in the vagus nerve), where they are converted into neuropeptides that regulate various brain activities. These neuropeptides participate in molecular, behavioral, and autonomic alterations in response to these signals from the gut microbiota. The gut's functions of obtaining nutrients and energy, removing waste, and resisting harmful toxins and pathogens are jointly regulated by the ENS and trillions of symbiotic bacteria colonizing the gut.