The gut microbiota (GM), a highly complex micro-ecosystem residing within the host’s gastrointestinal tract, works in conjunction with the gut immune system to form a precise bidirectional regulatory network, that maintains symbiotic homeostasis and overall host health. Cumulative evidence has demonstrated that the critical impact of the bidirectional causal relationship between the GM and the gut immune system on host development and the dynamic progression of disease. However, many challenges remain in this research field, including the mechanism complexity, therapeutic effect differences due to individual heterogeneity, long-term safety, and clinical transformation bottlenecks) that need to be urgently broken through. Therefore, the in-depth analysis of these issues is of great theoretical and practical significance for clarifying the intrinsic connection between the GM and gut immunity, particularly in elucidating the pathogenesis of related clinical diseases such as inflammatory bowel disease (IBD), tumors, and autoimmune diseases (AD). We systematically outline the interaction mechanisms between the microbiota and the immune system, including compositional structure (microbiota diversity and immune system composition), development and maturation processes (early microbiota colonization and immune system establishment), and functional regulation (immune cell differentiation and maintenance of mucosal barrier integrity), as well as their associations with clinical diseases. Finally, we discuss some key considerations for the developing of innovative treatment strategies, such as microbial-targeted interventions, fecal microbiota transplantation (FMT), and synergistic use of immunomodulatory drugs, with the aim of providing a new paradigm for the precise intervention of related diseases. GM-immune axis serves as the core driving force for host development and disease intervention. Interaction pattern between the GM and the immune system was dynamic across the dimensions of “composition-development-function.” The vicious cycle of GM and immune imbalance is with heterogeneity in different clinical diseases such as IBD, tumors, and autoimmune disorders.
Liu et al. (2026) studied this question.