Neuropeptide Y Receptor Modulators in Gut Physiology and Therapy

Introduction: Gut-brain communication depends on neuropeptides and hormones, and the Neuropeptide Y (NPY) family, which includes NPY, Peptide YY (PYY), and Pancreatic Polypeptide (PP), plays an important role. These peptides also affect gastrointestinal (GI) motility, secretion, nutrient uptake, and intestinal development. Diseases, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), gastroparesis, and obesity, are attributed to disruptions in this signaling axis. In this review, the physiological and pathological functions of NPY and its receptor subtypes (Y1, Y2, Y4, Y5) in the GI tract, the therapeutic potential of Pharmacological and natural modulators of this pathway are evaluated. Methods: An overview of recent experimental, clinical, and pharmacological evidence was carried out to describe receptor-specific activity, delineate the underlying pathophysiology, and investigate the clinical implications of NPY modulation in gastrointestinal health and disease Results: Literature reveals that NPY signaling controls GI motility, secretion, and appetite via diverse receptor pathways. Low NPY levels are often linked with diarrheal manifestations of IBD, while PYY-mediated ileal brake supports enhanced nutrient absorption. New therapeutic strategies are promising: Y1 receptor agonists can reduce diarrhoea, Y1 antagonists can be useful in constipation, and Y2/Y5 modulators may be useful in some conditions, including obesity and gastroparesis. Discussion: The existing evidence confirms the role NPY receptors play in the GI homeostasis and disease pathology. The modeling of precision-based pharmacological interventions facilitates an enhanced comprehension of receptor-based interactions. Yet, the difference in the study design and the paucity of long-term clinical data are also significant weaknesses. Conclusion: The NPY system is an essential part of the gut-brain axis. Inhibition of Y-receptor pathways is an attractive approach to promote GI functionality and bridge therapeutic gaps in functional and inflammatory gastrointestinal diseases.