# Microbes in Health and Disease: Human Gut Microbiota
## 3 Multifunction of the Human Gut Microbiota
### The Gut-Brain Axis  
The gut microbiota also participates in the development and function of the central nerve system, as demonstrated in germ-free animal model experiments [83] and human studies [84]. For example, germ-free animal models exhibit decreased anxiety-like behaviors and impaired short-term recognition and working memory [83]. There are remarkable differences in the gut microbiota between healthy subjects and patients with neurodegenerative disorders (e.g., Parkinson's disease) [85]. In a recent comparative analysis of the gut microbiota between Parkinson's disease (PD) subjects and healthy cohabitants, a higher number in _Lactobacillus_ and a lower number in the group of _Clostridium coccoides_ and _Bacteroides fragilis_ were found in PD subjects [86]. Particularly, irritable bowel syndrome (IBS) caused by dysbiosis of the normal gut microbiota is typically associated with mental health disorders (e.g., anxiety and depression) [87].  
The mechanisms of modulation by the gut microbiota are executed via the gut-brain axis, which involves bidirectional signaling communication [85]. Structurally, the axis includes the central nerve system (CNS), autonomic nerve system (ANS), enteric nerve system (ENS), hypothalamic pituitary adrenal (HPA) axis, circulatory system, immune system, and gut microbiota [85] (as shown in Figure 4). In addition, the neuronal, endocrine, and immune pathways are involved [85]. Firstly, the gut microbiota can modulate the responses of the central nervous system via direct or indirect control of key neurotransmitters (e.g., \(\gamma\)-aminobutyric acid (GABA), dopamine, and serotonin). The gut microbiota can directly synthesize neurotransmitters and their precursors and regulate the biosynthesis of neurotransmitters [85; 88]. The GABA producers include _Lactobacillus_, _Bifidobacterium_, and _Escherichia coli_; the dopamine producers include _Proteus vulgaris_, _Serratia marcescens_, and _Staphylococcus aureus_; and the serotonin producers include _E. coli_, _Streptococcus_, and _Enterococcus_[89]. The gut microbiota is involved in the metabolism of tryptophan, which is the precursor of serotonin [89]. Indigenous gut spore-forming bacteria can also pro mote the biosynthesis of serotonin in colonic enterochromaffin cells via the action of their metabolites [90]. Secondly, the gut microbiota not only plays an important role in the development of the HPA axis [91] but also regulates the activity of the HPA axis, which is the major neuroendocrine system in response to stressors, through the action of gut microbiota-associated substances such as bacterial antigens (e.g., lipopolysaccharidesaccharides), proinflammatory cytokines caused by dysbiosis of the gut microbiota, and short-chain fatty acids produced by gut bacteria fermenters [92]. Thirdly, the gut microbiota controls the maturation and function of microglia [93], which represent the largest population of immune cells in the brain and are essential for brain development and homeostasis [94, 95]. Moreover, the gut microbiota can activate immune cells (e.g., macrophages, neutrophils, and dendritic cells) to release proinflammatory cytokines (e.g., IL-1P, TNF\(\alpha\), and IL-6) via microbe-associated molecular patterns (MAMPs, e.g., lipopolysaccharidesaccharides), these cytokines cross the blood-brain barrier, enter the brain, activate microglia to release proinflammatory cytokines, and amplify the effects of cytokines on the CNS [96]. Moreover, proinflammatory cytokines can activate the kynure pathway and decrease the level of serotonin, affecting the response of the CNS [97]. Additionally, gut microbiota-associated substances (e.g., bile acids, peptidoglycan, lipopolysaccharidesaccharide, and toxins) can directly enter the CNS and regulate the response of the CNS [98].