Reframing type 1 diabetes through the endocannabinoidome-microbiota axis: a systems biology perspective

Type 1 diabetes (T1D) has long been recognized as a T-cell-driven autoimmune disease. However, growing evidence highlights the involvement of metabolic, inflammatory, and gut microbiota-related factors in its progression. The endocannabinoid system (ECS), a key regulator of immune and metabolic homeostasis, has been increasingly implicated in autoimmune pathophysiology, particularly through its interactions with gut-derived metabolites. This hypothesis article underscores the need to reframe T1D pathophysiology by integrating ECS dysfunction, gut dysbiosis, and metabolic imbalances into a systems biology framework. The proposed Endocannabinoidome-Microbiota (ECBoM) model highlights a shared hallmark of autoimmunity-SCFA depletion, increased intestinal permeability, and ECS dysregulation-as key drivers of chronic inflammation and immune dysfunction. These disturbances, observed in T1D as well as in celiac disease, Hashimoto's thyroiditis, rheumatoid arthritis, and multiple sclerosis, suggest a common immune-metabolic axis across autoimmune disorders. Recognizing ECS dysregulation as a systemic feature of autoimmunity opens avenues for novel therapeutic interventions, including ECS-targeted treatments, microbiota modulation, and phytocannabinoid-based therapies. This article highlights the necessity of conducting large-scale, multi-omics studies to establish disease-specific ECS signatures, linking endocannabinoid profiling, microbiota composition, and metabolic biomarkers to disease progression. By advocating for a paradigm shift in T1D research, this article emphasizes the importance of exploring new mechanistic references to develop targeted, immune-metabolic interventions that could reshape treatment strategies and improve clinical outcomes in T1D and related autoimmune diseases.