Gut microbiota-host adaptive immune interactions in type 2 diabetes mellitus: mechanisms, disease progression, and microbiota-based therapeutic strategies.

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder whose development and progression are influenced not only by genetic susceptibility, obesity, and lifestyle-related factors but also by gut microbiota dysbiosis, chronic low-grade inflammation, and disruption of immunometabolic homeostasis. The gut microbiota regulates adaptive immune responses through diverse signals, including microbial structural components, metabolites, extracellular vesicles, and other secreted molecules. These microbial-derived signals modulate antigen presentation, T-cell differentiation, B-cell function, and IgA-mediated mucosal immunity, thereby influencing adaptive immune populations such as Th1 cells, Th17 cells, CD8+ T cells, and regulatory T cells (Tregs). Conversely, the adaptive immune system can reshape microbial composition and functional outputs by regulating intestinal barrier integrity, mucosal immune homeostasis, and ecological niche stability, forming a dynamic and bidirectional gut microbiota-adaptive immunity interaction network. This reciprocal interaction persists throughout the progression from metabolic risk accumulation and insulin resistance to T2DM onset and diabetic complications, contributing to chronic low-grade inflammation, impaired insulin signaling, and pancreatic β-cell dysfunction. Unlike previous reviews that have primarily focused on gut microbiota dysbiosis, microbial metabolites, or innate immune regulation, this review highlights the bidirectional interactions between the gut microbiota and adaptive immunity as a central framework. We systematically summarize the underlying molecular mechanisms, dynamic disease evolution, and advances in microbiota-targeted therapeutic strategies. In recent years, dietary modulation, probiotics, prebiotics, synbiotics, postbiotics, fecal microbiota transplantation, and engineered microbiome-based therapies have emerged as potential approaches targeting the microbiota-immune axis. Among these strategies, dietary interventions and certain microbiota-based supplements have obtained preliminary clinical support, whereas fecal microbiota transplantation, engineered bacteria, and phage-based therapies remain under active investigation. However, clinical translation of microbiome-targeted therapies is still challenged by interindividual microbiota heterogeneity, insufficient standardization of interventions, uncertain long-term safety, and limited causal evidence. Future efforts should integrate microbial composition, functional metabolic profiles, adaptive immune signatures, and host metabolic states to achieve precise patient stratification and facilitate the development of personalized microbiome-based interventions. This review provides a conceptual framework for understanding immunometabolic mechanisms in T2DM and offers new perspectives for precision therapeutic strategies.