# 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
#### 3.2.5 Endocannabinoid System  
In 2017, researchers discovered that human gut bacteria produce N-acyl amide, which structurally mimics the host's endogenous bioactive lipids within the endocannabinoid system (ECS) and interacts with several host receptors in the gastrointestinal (GI) tract [104]. Notably, some of these microbial metabolites function as potent agonists of GPR119, a receptor regulating glucose and energy metabolism. For instance, oleoplethanolamide and 2-oleoyl glycerol (2-OG) [105], both endogenous ligands of GPR119, are ECS members that stimulate GLP-1 secretion by activating GPR119 on enteroendocrine L-cells, consequently influencing glucose and energy metabolism. Investigating the physiological effects of microbial N-acyl amides, [PERSON] et al. [105] administered an engineered bacterium-produced N-acyl amide, specifically N-acyl serinol, to gnotobiotic mice and observed improved oral glucose tolerance compared to control mice, suggesting direct modulation of host physiology by microbial-derived N-acyl amide. However, whether microbiota-derived N-acyl amides act through paracrine or endocrine mechanisms remains uncertain. This fact raises questions regarding the modulation of intestinal ECS tone by the gut microbiome or vice versa. While this study highlights gut bacteria's ability to produce metabolites analogous to endocannabinoids, other studies support the existence of crosstalk between gut bacteria and the host's ECS. For example, administering _Akkermansia muciiphila_[106], a commensal bacterium known to prevent diet-induced obesity, increases the intestinal levels of several 2-acylglycerols, including 2-OG, 2-arachidonylglycerol, and 2-palmitoyl glycerol. Both 2-OG and 2-palmitoyl glycerol are implicated in controlling gut barrier function and inflammation, as they activate GPR119 and stimulate GLP-1 secretion [107; 108] (Figure 2). Figure 1: The microbiota-produced short-chain fatty acids (SCFAs) are crucial in modulating host endocrine functions. They impact host metabolism by interacting with receptors expressed by intestinal enteroendocrine L-type cells locally and distally in organs such as the liver, adipose tissue, brain, and muscle. Also, gut microbes contribute to host metabolism by producing neurotransmitters like histamine, serotonin, GABA, and gaseous neurotransmitters. These microbial neurotransmitters influence host physiology and shape interactions among bacteria, affecting microbial adaptation and disease development. However, the origin of these 2-acylglycerols, whether derived from bacteria or the host, remains unclear. Variances in gut microbiome composition have been linked to changes in intestinal ECS, impacting gut permeability and endotoxemia. Various approaches aimed at modulating gut microbiome composition, such as high-fat diets, prebiotics, probiotics, antibiotics, or germ-free mice, have shown colon-specific modulation of CB1 receptor expression and alterations in bioactive lipid levels and ECS enzyme expression in the colon [109,110]. Deleting the main endocannabinoid-synthesising enzyme from intestinal epithelial cells in mice alters gut microbiome composition. Many questions remain unanswered despite these findings revealing a direct correlation between intestinal ECS and the gut microbiome. For instance, does gut microbiome composition variation modulate ECS tone, or does modulation of intestinal endocannabinoid tone drive changes in gut microbiome composition? Notably, intestinal endocannabinoids play a role in modulating peristalsis and food intake, suggesting that the host's ECS may shape gut microbiome composition by modulating these variables [111]. The interaction between ECS and the gut microbiome extends beyond the intestine. Modifications in gut microbiome composition, induced by prebiotics and antibiotics, have been shown to modulate bioactive lipid levels and ECS receptor and enzyme expression in adipose tissue, impacting obesity and metabolic disorders.