International Journal of Molecular Medical Science, 2024, Vol.14, No.2, 106-122 http://medscipublisher.com/index.php/ijmms 107 et al., 2015; Wiley et al., 2017; Martin et al., 2018). This targeted modulation holds potential for developing novel therapeutic strategies for mental health disorders. This study article aims to deeply explore the potential of engineered synthetic microbial communities (SynComs) in regulating neurotransmitter production and improving mental health. By comprehensively analyzing existing research on the gut-brain axis and the impact of the gut microbiota on neuropsychiatric disorders, this article reveals how SynCom interventions can influence brain function and behavior. Key findings from preclinical and clinical studies are highlighted, mechanisms of gut-brain communication are discussed, and gaps in the current knowledge base are identified to guide future research. This study emphasizes the importance of SynComs as an innovative and promising therapeutic approach for the prevention and treatment of mental health issues, providing a theoretical foundation for future research and clinical practice. 2 The Gut-Brain Axis: A Complex Communication Network 2.1 Definition and components of the Gut-Brain axis The gut-brain axis (GBA) is a bidirectional communication network that links the gastrointestinal (GI) tract and the central nervous system (CNS). This axis encompasses various components, including the enteric nervous system (ENS), the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal (HPA) axis, and the gut microbiota (Martin et al., 2018; Cryan et al., 2019; Hattori and Yamashiro, 2021). The ENS, often referred to as the "second brain", resides within the intestinal wall and communicates with the brain via the vagus nerve and other neural pathways (Hattori and Yamashiro, 2021). The ANS, comprising sympathetic and parasympathetic branches, modulates gut motility, secretion, and permeability, thereby influencing the gut microbiota (Martin et al., 2018). The HPA axis plays a crucial role in stress responses, linking the gut and brain through hormonal signaling (Hattori and Yamashiro, 2021). Collectively, these components form a complex network that maintains homeostasis and influences both gut and brain functions. 2.2 Mechanisms of communication between the gut and the brain The communication between the gut and the brain occurs through multiple mechanisms, including neural, endocrine, and immune pathways (Figure 1). The vagus nerve is a primary neural conduit for gut-brain communication. It transmits signals from the gut to the brain and vice versa, playing a crucial role in regulating gut motility, secretion, and immune responses. The ENS also communicates directly with the CNS through intrinsic primary afferent neurons that detect changes in the gut environment (Bistoletti et al., 2020). The research of Ma et al. (2019) shows the interaction between the gut microbiota and the gut-brain axis through various mechanisms, affecting the health of the central nervous system. Short-chain fatty acids regulate immune cells, promoting anti-inflammatory responses; microglial cell maturation is impaired under germ-free conditions, affecting neuroprotection; specific probiotics promote hippocampal neurogenesis; blood-brain barrier permeability increases under germ-free conditions but can be restored to normal function by microbial colonization or short-chain fatty acids; the vagus nerve directly and indirectly influences brain function by transmitting neural signals and metabolites. These mechanisms highlight the crucial role of gut microbiota in maintaining and regulating central nervous system health. The HPA axis mediates the endocrine communication between the gut and the brain. In response to stress, the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to secrete adrenocorticotropic hormone (ACTH). ACTH then prompts the adrenal glands to release cortisol, a hormone that influences gut permeability and immune function. Additionally, gut hormones such as ghrelin, peptide YY, and glucagon-like peptide-1 (GLP-1) can signal the brain to regulate appetite and metabolism (Makris et al., 2021). The immune system is a key player in the gut-brain axis. Gut-associated lymphoid tissue (GALT) monitors and responds to pathogens and other antigens in the gut. Immune cells release cytokines that can influence brain function and behavior. Chronic inflammation in the gut can lead to increased permeability of the blood-brain barrier, allowing immune signals to affect the brain directly. This interaction is bidirectional, as brain inflammation can also impact gut health and microbiota composition (Fung, 2020).
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