Exploring the complex interplay: insulin resistance and gut microbiome dysbiosis in multiple sclerosis

Multiple sclerosis (MS) is a progressive, autoimmune demyelinating disorder of the central nervous system (CNS), characterized by neurological impairments driven by complex interactions between genetic, immunological, and environmental factors. While the individual roles of insulin resistance (IR) and gut microbiome dysbiosis in MS have been explored, their synergistic interaction remains under-investigated. In this novel integrative review, we comprehensively examine the bidirectional crosstalk between IR and gut microbiota alterations, highlighting shared inflammatory and metabolic pathways; such as NLRP3 inflammasome activation, Th17/Treg imbalance, and blood-brain barrier disruption; that underpin neuroinflammation in MS. We identify emerging evidence suggesting that concurrent modulation of both IR and microbial composition may offer a more effective therapeutic strategy than targeting each independently. Furthermore, we propose a framework for personalized, microbiota-informed metabolic interventions (e.g., "probiotic-metformin combinatorial strategies"), grounded in recent findings from multi-omics studies and experimental autoimmune encephalomyelitis (EAE) models. This review aims to bridge existing knowledge gaps, provide a unified perspective on metabolic-immune-microbial interplay in MS, and stimulate new research directions toward holistic and precision medicine approaches for disease prevention and management.