Abstract Diabetes mellitus is traditionally conceptualized as a noncommunicable metabolic disorder driven by intrinsic defects in insulin secretion and insulin action. However, accumulating evidence indicates that systemic metabolic dysfunction may also arise from acquired ecological disturbances mediated by polymicrobial communities and their metabolic outputs. Recent advances in microbiome research have demonstrated consistent associations between gut dysbiosis, increased intestinal permeability, metabolic endotoxemia, and chronic low-grade inflammation, all of which are implicated in the development of insulin resistance. These findings challenge the traditional host-centric paradigm and support a broader ecological perspective of metabolic disease. Here, we propose a conceptual and mechanistic framework for Type 6 Diabetes Mellitus (T6DM), a putative clinical entity characterized by muscle-predominant insulin resistance (MPIR) associated with environmentally acquired diabetogenic polymicrobial fecal signatures (DPS). This model integrates central neuroimmune regulation, neurovascular mechanisms, skeletal muscle susceptibility, and gut microbiota dynamics within a hierarchical brain–muscle–gut axis. This framework suggests that, in a subset of individuals, metabolic dysfunction may represent a systems-level ecological condition rather than a purely intrinsic metabolic defect. Importantly, it raises the possibility that such conditions may be partially reversible through interventions targeting microbial ecology, intestinal barrier integrity, neuroinflammation, and behavioral factors. T6DM is proposed as a testable, falsifiable, and potentially reversible systems-level condition integrating microbial ecology, neuroimmune regulation, and host metabolic responses, providing a novel framework for precision-oriented metabolic research and intervention.
Amorim et al. (Tue,) studied this question.