Short chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are produced by intestinal bacteria from undigested dietary carbohydrates. These SCFAs play crucial roles in regulating intestinal energy metabolism, maintaining gut homeostasis, and influencing various organs and tissues outside the gut. Recent studies have highlighted their regulatory roles in inflammation and host health through two main signaling mechanisms: activation of G-protein coupled receptors (GPCRs) and inhibition of histone deacetylase (HDAC). SCFAs are vital mediators between the microbiota and host physiology, with decreased production associated with metabolic diseases. They influence a wide range of diseases, including gastrointestinal disorders, obesity, diabetes, inflammation, kidney disease, cancer, and neurological disorders. The production of SCFAs involves complex microbial fermentation pathways, and they are rapidly absorbed by colonocytes before being transported through the bloodstream to various parts of the body. SCFAs have been shown to modulate immune responses by regulating T-cell polarization and inducing the differentiation of effector and regulatory T cells (Tregs). They also act as HDAC inhibitors, which can influence metabolic and inflammatory processes. SCFAs regulate inflammation by acting on GPCRs and HDAC. For example, acetate activates GPR43, which reduces pro-inflammatory cytokine production and modulates immune responses. Propionate and butyrate, through their effects on HDAC, can promote the production of Tregs and reduce inflammation. However, the pro-inflammatory effects of SCFAs have also been observed, particularly in neutrophils. The physiological and pathological effects of SCFAs vary depending on their concentration and type. Acetate, the most abundant SCFA, has protective effects against colitis, neurodegeneration, and pancreatic inflammation. Propionate promotes metabolic benefits and protects against cardiac damage and atherosclerosis. Butyrate, the preferred energy source for colon cells, is crucial for maintaining intestinal barrier function and inflammation. It also exhibits anti-inflammatory properties and has therapeutic potential in obesity, diabetes, cancer, kidney diseases, and neurological disorders. Despite the growing evidence of SCFAs' benefits, some mechanisms remain unclear, such as the opposing pro-inflammatory and anti-inflammatory effects of SCFAs in certain contexts. Further research is needed to fully understand the complex interactions of SCFAs in physiology and pathology. Natural herbal medicines, such as mulberry leaves, have shown promise in regulating gut microbiota and improving health by increasing SCFA levels and modulating immune responses.Short chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are produced by intestinal bacteria from undigested dietary carbohydrates. These SCFAs play crucial roles in regulating intestinal energy metabolism, maintaining gut homeostasis, and influencing various organs and tissues outside the gut. Recent studies have highlighted their regulatory roles in inflammation and host health through two main signaling mechanisms: activation of G-protein coupled receptors (GPCRs) and inhibition of histone deacetylase (HDAC). SCFAs are vital mediators between the microbiota and host physiology, with decreased production associated with metabolic diseases. They influence a wide range of diseases, including gastrointestinal disorders, obesity, diabetes, inflammation, kidney disease, cancer, and neurological disorders. The production of SCFAs involves complex microbial fermentation pathways, and they are rapidly absorbed by colonocytes before being transported through the bloodstream to various parts of the body. SCFAs have been shown to modulate immune responses by regulating T-cell polarization and inducing the differentiation of effector and regulatory T cells (Tregs). They also act as HDAC inhibitors, which can influence metabolic and inflammatory processes. SCFAs regulate inflammation by acting on GPCRs and HDAC. For example, acetate activates GPR43, which reduces pro-inflammatory cytokine production and modulates immune responses. Propionate and butyrate, through their effects on HDAC, can promote the production of Tregs and reduce inflammation. However, the pro-inflammatory effects of SCFAs have also been observed, particularly in neutrophils. The physiological and pathological effects of SCFAs vary depending on their concentration and type. Acetate, the most abundant SCFA, has protective effects against colitis, neurodegeneration, and pancreatic inflammation. Propionate promotes metabolic benefits and protects against cardiac damage and atherosclerosis. Butyrate, the preferred energy source for colon cells, is crucial for maintaining intestinal barrier function and inflammation. It also exhibits anti-inflammatory properties and has therapeutic potential in obesity, diabetes, cancer, kidney diseases, and neurological disorders. Despite the growing evidence of SCFAs' benefits, some mechanisms remain unclear, such as the opposing pro-inflammatory and anti-inflammatory effects of SCFAs in certain contexts. Further research is needed to fully understand the complex interactions of SCFAs in physiology and pathology. Natural herbal medicines, such as mulberry leaves, have shown promise in regulating gut microbiota and improving health by increasing SCFA levels and modulating immune responses.