# Gut Microbiota as an Endocrine Organ: Unveiling Its Role in Human Physiology and Health
## 3 Neurohormones and Their Role in Microbial Effects
### Neurohormones: Bridging the Gap between the Brain and Microbial Effects
#### 3.2.4 The Impact of Short-Chain Fatty Acids (SCFAs) and Its Implications for Neurological Health  
Beyond vagal-mediated pathways, bidirectional communication between gut microbes and the CNS involves SCFAs, the immune system, and the hypothalamic-pituitary-adrenal (HPA) axis. Modes of interaction through the microbiota-gut-brain axis link cognitive, emotional, and reward centres in the brain with visceral signals from the gut. The gut microbiota metabolises complex, indigestible carbohydrates in the large intestine through anaerobic fermentation, producing short-chain fatty acids (SCFAs) [96]. The main SCFAs, including butyrate (C4), propionate (C3), and acetate (C2), vary among individuals based on specific microbial abundance and have been shown to control systemic inflammation, maintain intestinal barrier integrity, and facilitate gut-brain communication. For example, inoculating germ-free mice with _Clostridium butyricum_ and _Bacteroides thetaito-taomicron_ reduced blood-brain barrier permeability by upregulating the expression of brain tight junction proteins [97]. Additionally, certain SCFAs, particularly butyrate, are integral to gut-brain signalling, influencing neurotransmitter levels and functioning. Butyrate, in particular, is associated with gastrointestinal health, neurotransmitter concentrations, and gut-brain communication. Colonic enterocytes utilise butyrate, primarily produced by Firmicutes genera like _Clostridium_, _Rumminococcus_, _Eubacterium_, and _Faecalibacterium_, as their primary energy source [98]. Butyrate's intrinsic histone deacetylase (HDAC) inhibitor activity affects neurotransmitter levels, making it a crucial component of gut-brain signalling. Sodium butyrate, a prominent HDAC inhibitor, has been shown to benefit neurotoxicity-induced rats, improving locomotor symptoms and increasing striatal dopamine [99]. HDAC inhibition by sodium butyrate has demonstrated positive effects on \(\alpha\)-synuclein damage and the rescue of dopaminergic cells in Parkinson's disease (PD) models [100]. Moreover, butyrate and other SCFAs modulate microglial activity, influencing neuroinflammation and oxidative stress. The role of butyrate in influencing microglial activation and proinflammatory cytokine release is of particular interest in comprehending the influence of gut microbes on neurodegenerative disorders characterised by dopaminergic neuron degeneration, such as PD. Propionate, another SCFA produced by _Bacteroides_ and _Frimicutes_, has also been associated with gut-brain communication [101]. Propionate activates intestinal gluconeogenesis, implicating it in reducing food intake and weight gain. Interestingly, a study found that propionate activates intestinal gluconeogenesis genes, leading to glucose production and influencing appetite regulation through gut-brain signalling [44]. Although the exact mechanisms through which propionate affects the gut-brain axis are not entirely elucidated, its potential role in metabolic regulation and its influence on neural circuits involved in appetite and reward warrant further investigation. Acetate, the third major SCFA, is produced by several bacterial species, including _Bifidobacterium_, _Clostidium_, _Bacteroides_, and _Akkermansia_[102]. Although acetate has not received as much attention as butyrate and propionate in gut-brain communication, it regulates energy balance and metabolism. Acetate traverses the blood-brain barrier and could contribute to central appetite regulation and energy homeostasis [103]. Because of its role as a signalling molecule, it engages with G-protein-coupled receptors (FFAR2 and FFAR3) to regulate appetite. SCFAs bind to G protein-coupled receptors (GPCRs) like GPR-43 and GPR-41 and are expressed in various tissues, including enteroendocrine L-cells. When activated by SCFAs, these receptors promote the secretion of gut peptides like GLP-1 and PYY, activating central satiety circuits and emphasising the role of the microbiome in controlling gut peptide production (Figure 1).