Motilin

Endogenous Hormone

Motilin is a 22-amino-acid peptide hormone secreted mainly by specialized endocrine cells (M-cells) in the mucosa of the duodenum and upper jejunum. Its defining role is as the principal driver of the migrating motor complex (MMC), the cyclical pattern of electrical and mechanical activity that governs gut motility during fasting. In particular, motilin triggers phase III of the MMC — the intense front of contractions, sometimes called the "intestinal housekeeper" or "housekeeper wave," that begins in the stomach and sweeps down the small intestine, clearing residual food, secretions, and bacteria between meals. Plasma motilin rises and falls in a cyclical rhythm during fasting that closely parallels these phase III bursts, and eating suppresses this pattern until the next interdigestive period. Motilin acts through the motilin receptor (MLNR, also known as GPR38), a G protein-coupled receptor expressed on enteric neurons and gastrointestinal smooth muscle. Activation of this receptor initiates the coordinated contractions of phase III. A key point of clinical interest is that the antibiotic erythromycin, and related macrolide compounds known as "motilides," are agonists at the motilin receptor. This off-target property explains why low-dose erythromycin is used as a prokinetic agent to stimulate gastric emptying in conditions such as gastroparesis: it mimics motilin at the receptor and accelerates gut motility, independent of any antibacterial effect. Motilin is an endogenous hormone — it is produced by the body and is not sold or administered as an approved drug in its native peptide form. Its importance in medicine lies less in motilin itself than in what it teaches about designing prokinetic therapies. Because native motilin is impractical as a drug and long-term macrolide use raises concerns about tachyphylaxis and antibiotic resistance, considerable research has focused on developing selective, non-antibiotic motilin receptor agonists as potential treatments for disorders of delayed gastric emptying and impaired motility. Several such candidates have been studied, though outcomes have been mixed and none has become a mainstay of therapy. Understanding motilin is central to understanding fasting-state gut physiology and the broader field of prokinetic pharmacology. It is best studied alongside the migrating motor complex it controls and alongside ghrelin, a structurally related peptide whose receptor agonists (such as the investigational prokinetic relamorelin) are being explored for similar motility indications. Together, the motilin and ghrelin systems illustrate how the gut coordinates its rhythmic activity and how that biology can, in principle, be harnessed to treat motility disorders.