Serotonergic signaling in gastric physiology and motility disorders.

Abstract

Serotonin (5-hydroxytryptamine; 5-HT) is a key regulator of gastrointestinal function and exerts its effects through a diversity of 5-HT receptors. In the gut, 5-HT is released primarily by enterochromaffin cells, which act as specialized epithelial chemo- and mechanosensors. In humans, 5-HT modulates gastric sensorimotor function, and animal studies suggest that it is involved in enteric neurogenesis. Altered serotonergic signalling is increasingly recognized as an important contributor to the pathophysiology of gastric motility disorders and therefore represents an important therapeutic target. Although early serotonergic agents such as cisapride were withdrawn due to safety concerns, newer receptor-specific ligands have become available, broadening the therapeutic landscape and underscoring the need for an updated synthesis of serotonergic pathways and therapies in gastric motility disorders. For the management of GP, 5-HT4 agonists are the most consistently supported serotonergic agents in international guidelines, with evidence for improving gastric emptying and symptoms, while 5-HT3 antagonists are primarily used for symptomatic control of nausea and vomiting. In FD, serotonergic therapies may be selectively considered for off-label use based on the symptom profile, including mirtazapine (5-HT2 antagonist) in patients with early satiety and weight loss, and buspirone (5-HT1A agonist) in those with early satiety, postprandial fullness or bloating. Although selective serotonin reuptake inhibitors (SSRI) and serotonin-noradrenaline reuptake inhibitors (SNRI) are not recommended for use in GP or FD, their potential role warrants further investigation, particularly given their established efficacy in conditions with chronic pain. Large controlled trials evaluating the efficacy of serotonergic agents in GP and FD remain lacking, but recent developments highlight the continued relevance of serotonergic modulation. Recent data on naronapride, a newer 5-HT4 agonist, suggest that more selective agents may offer clinically relevant benefit while mitigating cardiovascular safety risks associated with earlier agents. By integrating molecular, physiological, and clinical data, this review aims to clarify the relevance of serotonergic signaling in gastric physiology and motility disorders, define its therapeutic applications, and identify key remaining evidence gaps.