Serotonergic Signaling in Gastric Physiology and Motility Disorders

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 signaling 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 Although early serotonergic agents such as cisapride were withdrawn due to safety concerns, newer receptor-specific ligands have become available, broadening the therapeutic landscape and underscoring the need for an updated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 gastroparesis, 5-HT₄ agonists are the most consistently supported serotonergic agents in international guidelines, with evidence for improving gastric emptying and symptoms, and 5-HT₃ antagonists are used primarily for symptomatic control of nausea and vomiting. In functional dyspepsia, serotonergic therapies may be selectively considered for off-label use based on the symptom profile, including mirtazapine (a 5-HT₂ antagonist) in patients with early satiety and weight loss, and buspirone (a 5-HT_1A agonist) in those with early satiety, postprandial fullness, or bloating. Although selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors are not recommended for use in gastroparesis or functional dyspepsia, 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 gastroparesis and functional dyspepsia 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 a 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 the key remaining evidence gaps.