Resident microbes shape host immunity and protect against pathogen infection and inflammatory disease.

The gastrointestinal tract harbors a vast and diverse community of microorganisms that establish a mutualistic and stable relationship with the host. These resident microbes play critical roles in protecting the host from luminal antigens, particularly pathogenic and opportunistic microorganisms, while simultaneously contributing to intestinal homeostasis. Accumulating evidence indicates that the gut microbiota profoundly shapes the development, differentiation, and function of epithelial and immune cells through coordinated molecular and cellular interactions. Recent studies have highlighted that barrier formation and immune homeostasis in the intestine are not solely host-driven processes but rather arise from cooperative interactions between resident microorganisms and host epithelial and immune compartments. Microbiota-derived signals promote epithelial integrity and instruct innate and adaptive immune responses, collectively establishing a robust yet tightly regulated infection-defense system that suppresses intestinal inflammation and maintains immune homeostasis. In this review, we focus on the role of the gut microbiota in the development of the host immune system, especially innate and adaptive lymphocytes, including epithelial cells, innate lymphoid cells, Th17 cells, and IgA+ B cells. We discuss how resident microorganisms shape these immune components to form a protective barrier system that not only confers resistance to pathogenic and opportunistic microbial infections but also maintains local and systemic immune homeostasis. Furthermore, we address how disruption of these microbiota-driven regulatory networks can contribute to the development of inflammatory diseases, highlighting the importance of host-microbiota interactions in health and disease.