Irritable bowel syndrome (IBS) is a common, often disabling disorder of gut-brain interaction whose molecular basis remains incompletely defined, leaving diagnosis largely symptom-based and treatment largely non-mechanistic. We argue that the serotonin (5-hydroxytryptamine; hereafter 5-HT, the primary term used throughout, with "serotonin" retained in less technical contexts) signalling axis-positioned at the interface of the gut microbiota, enterochromaffin (EC) cells, enteric neurons, and the mucosal immune system-is a central, unifying integrator of IBS pathophysiology, and that reframing IBS around this axis offers a route toward mechanism-based subtyping and therapy. We first synthesise how microbiota-driven tryptophan metabolism, short-chain fatty acid and secondary bile acid signalling, and epigenetic regulation of tryptophan hydroxylase 1 (TPH1) shape EC-cell serotonin output, before examining the neuroimmune consequences of dysregulated serotonin secretion-mast cell activation, macrophage polarisation, neurogenic inflammation-and the microbiota-serotonin-gut-brain connectome linking vagal afferent signalling, blood-brain barrier permeability, and central neurotransmitter networks. We then discuss molecular stratification of IBS subtypes through serotonergic endotyping-incorporating SLC6A4 and TPH1 polymorphisms, single-cell transcriptomics, and spatial metabolomics-and critically evaluate next-generation therapeutic strategies, including engineered probiotic chassis, CRISPR-mediated microbial editing, and AI-guided nanomedicine, distinguishing proof-of-concept findings from clinically validated approaches. We conclude that reconceptualising IBS as a disorder of disrupted microbial serotonergic ecosystems, rather than a purely symptom-defined syndrome, offers a coherent and testable framework for biomarker discovery and precision, mechanism-directed therapy, while highlighting the causal-directionality and clinical-translation gaps that must be closed before