The Enterolimbic Axis: Gut-Brain Affective Circuits at the Crossroad of Metabolism, Emotion, and Behavior

The enterolimbic axis represents a novel conceptual framework which redefines gut-brain interactions by integrating gastrointestinal physiology, microbiota, incretin signaling, and affective regulation. Recent advances demonstrate that gut-derived signals influence reward processing, eating behavior, and emotional states through hierarchical circuits linking the enteric nervous system, vagal afferents, and limbic regions. Short-chain fatty acids (SCFAs) and incretins such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide modulate hypothalamic and mesolimbic pathways, highlighting the gut as a central regulator of metabolism. GLP-1 receptor agonists and dual gastric inhibitory polypeptide/GLP-1 agonists demonstrate profound effects on weight reduction, glycemic control, and hedonic eating, suggesting their early adoption in managing obesity, metabolic dysfunction-associated steatotic liver disease, type 2 diabetes, and binge eating disorders. We propose that gastroenterologists embrace these agents as first-line therapies, leveraging the unique endocrine role of the gut in metabolic regulation. This review integrates molecular, clinical, and therapeutic insights to outline diagnostic and precision-medicine opportunities arising from enterolimbic modulation.