The gut microbiota plays a crucial role in regulating inflammatory responses through interactions with the immune system, particularly via the G-protein-coupled receptor GPR43. Short-chain fatty acids (SCFAs), produced by gut bacteria from dietary fiber, bind to GPR43 and modulate immune responses. GPR43-deficient mice exhibit exacerbated or unresolved inflammation in models of colitis, arthritis, and asthma, indicating that GPR43 is essential for normal immune resolution. SCFAs enhance the function of immune cells, including neutrophils and eosinophils, by activating GPR43, which reduces inflammation and promotes immune cell recruitment. Germ-free mice, lacking bacteria and SCFAs, show similar inflammatory dysregulation, highlighting the link between diet, gut microbiota, and immune responses. SCFAs, particularly acetate and propionate, have anti-inflammatory effects on both epithelial cells and immune cells. GPR43 is expressed in immune cells and colonic epithelium, and its activation by SCFAs influences inflammatory responses. In experiments, GPR43-deficient mice showed increased inflammation in colitis models, while acetate treatment reduced inflammation. GPR43 is also involved in inflammatory arthritis and allergic airway disease, with GPR43-deficient mice showing more severe symptoms. The study demonstrates that GPR43 is a key receptor for SCFA-mediated regulation of immune responses, and that SCFA-GPR43 signaling is a molecular pathway by which gut microbiota influences immune and inflammatory diseases. The findings suggest that modulating gut microbiota and SCFA levels could be a therapeutic strategy for inflammatory diseases.The gut microbiota plays a crucial role in regulating inflammatory responses through interactions with the immune system, particularly via the G-protein-coupled receptor GPR43. Short-chain fatty acids (SCFAs), produced by gut bacteria from dietary fiber, bind to GPR43 and modulate immune responses. GPR43-deficient mice exhibit exacerbated or unresolved inflammation in models of colitis, arthritis, and asthma, indicating that GPR43 is essential for normal immune resolution. SCFAs enhance the function of immune cells, including neutrophils and eosinophils, by activating GPR43, which reduces inflammation and promotes immune cell recruitment. Germ-free mice, lacking bacteria and SCFAs, show similar inflammatory dysregulation, highlighting the link between diet, gut microbiota, and immune responses. SCFAs, particularly acetate and propionate, have anti-inflammatory effects on both epithelial cells and immune cells. GPR43 is expressed in immune cells and colonic epithelium, and its activation by SCFAs influences inflammatory responses. In experiments, GPR43-deficient mice showed increased inflammation in colitis models, while acetate treatment reduced inflammation. GPR43 is also involved in inflammatory arthritis and allergic airway disease, with GPR43-deficient mice showing more severe symptoms. The study demonstrates that GPR43 is a key receptor for SCFA-mediated regulation of immune responses, and that SCFA-GPR43 signaling is a molecular pathway by which gut microbiota influences immune and inflammatory diseases. The findings suggest that modulating gut microbiota and SCFA levels could be a therapeutic strategy for inflammatory diseases.