GLP-1/GLP-1R signalling in infectious diseases: basic biology, immunometabolic mechanisms, and therapeutic translation

Abstract Infectious diseases remain a major global health burden, and metabolic disorders such as diabetes and obesity further increase susceptibility to infection and adverse outcomes. These intersecting metabolic and infectious risks have prompted growing interest in the glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) axis beyond its established role in glycaemic regulation. GLP-1 receptor agonists (GLP-1RAs) modulate systemic metabolism, neuroimmune signalling, vascular and epithelial homeostasis, and inflammatory responses. Whether their infection-related effects arise from direct immune-cell GLP-1R signalling, improved pathogen control, or indirect host protection remains unresolved. This narrative review critically evaluates GLP-1/GLP-1R signalling in infection. It distinguishes live-pathogen models from endotoxin and sterile-injury models, host resistance from host tolerance, and direct receptor-dependent actions from indirect systemic effects. It also differentiates chronic pre-infection exposure from treatment initiated after infection onset. Across selected preclinical models, GLP-1RAs more consistently attenuate inflammation and tissue injury while preserving organ function, whereas their effects on pathogen burden and clearance remain variable. Receptor-specific evidence for immune-cell-intrinsic GLP-1R signalling remains limited, and many reported immune phenotypes may instead reflect metabolic improvement, neuroimmune regulation, or barrier protection. Human evidence is derived mainly from observational studies and secondary analyses of chronic GLP-1RA exposure, with limited evidence from trials initiating treatment during acute infection. Future translation will require cell-specific receptor validation, live-pathogen models with post-infection treatment, parallel assessment of pathogen control and host protection, clinically relevant standard-of-care comparators, and infection-specific safety evaluation. GLP-1RAs are therefore best regarded as candidate host-directed adjuncts. Current evidence does not establish them as direct anti-infective therapies.