The article reviews the complex interplay between the gut microbiome and the mammalian immune system, emphasizing its roles in health and disease. The microbiome plays a critical role in training and developing the host's innate and adaptive immune system, while the immune system maintains key features of host-microbe symbiosis. Imbalances in these interactions can lead to immune-mediated disorders, particularly in genetically susceptible individuals. The review highlights the importance of early-life colonization in shaping immune responses and the dynamic nature of these interactions. It discusses the mechanisms by which the microbiome and immune system communicate, including the roles of antimicrobial peptides, pattern recognition receptors, and inflammasomes. The impact of environmental factors such as diet and antibiotic use on microbiome composition and immune function is also explored. The article further examines the dysregulation of microbiome-immunity interactions in diseases like inflammatory bowel disease (IBD), rheumatoid arthritis, cardiometabolic diseases, and cancer. Finally, it touches on the role of extra-intestinal microbiota in modulating immunity in organs such as the skin, liver, and brain.The article reviews the complex interplay between the gut microbiome and the mammalian immune system, emphasizing its roles in health and disease. The microbiome plays a critical role in training and developing the host's innate and adaptive immune system, while the immune system maintains key features of host-microbe symbiosis. Imbalances in these interactions can lead to immune-mediated disorders, particularly in genetically susceptible individuals. The review highlights the importance of early-life colonization in shaping immune responses and the dynamic nature of these interactions. It discusses the mechanisms by which the microbiome and immune system communicate, including the roles of antimicrobial peptides, pattern recognition receptors, and inflammasomes. The impact of environmental factors such as diet and antibiotic use on microbiome composition and immune function is also explored. The article further examines the dysregulation of microbiome-immunity interactions in diseases like inflammatory bowel disease (IBD), rheumatoid arthritis, cardiometabolic diseases, and cancer. Finally, it touches on the role of extra-intestinal microbiota in modulating immunity in organs such as the skin, liver, and brain.