Gut microbiota-mediated metabolic dysregulation in type 2 diabetes and metabolic syndrome: emerging therapeutic targets beyond glycaemic control.
Metabolic diseases, particularly type 2 diabetes mellitus (T2DM) and obesity, have been traditionally understood through glucose-centric models. However, hyperglycaemia is a downstream consequence of systemic immune-metabolic dysregulation, with the gut microbiota acting as a central upstream regulator through defined molecular signalling pathways. This review examines four principal microbiota-host signalling axes through which ecological disruption drives systemic metabolic disease: short-chain fatty acid (SCFA) depletion impairing free fatty acid receptor (FFAR2/FFAR3) and AMP-activated protein kinase (AMPK) signalling; altered bile acid (BA) biotransformation perturbing farnesoid X receptor (FXR) and TGR5 signalling; increased intestinal permeability facilitating lipopolysaccharide (LPS) translocation and Toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-κB) activation; and diminished indole production reducing aryl hydrocarbon receptor (AhR)-driven interleukin-22 (IL-22) secretion. Therapeutic strategies targeting these pathways, including SCFA prodrugs, FXR modulators, TGR5 agonists, and next-generation probiotics, offer disease-modifying potential beyond glycaemic lowering and highlight the need for a multidimensional clinical endpoint framework spanning inflammatory, hepatic, and barrier biomarkers to enable comprehensive translational evaluation of microbiota-directed therapies.