Neuropilin-1 and the Gut Microbiome: Emerging Interactions Linking Intestinal Barrier Homeostasis, Immunomodulation and Metabolic Disorders

Metabolic disorders such as obesity, insulin resistance, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD) are increasingly linked to disruption of the gut microbiota and intestinal barrier function. Neuropilin-1 (NRP1), a transmembrane glycoprotein expressed on epithelial, endothelial, and immune cells, has recently emerged as a molecular nexus connecting the gut microbiome, immune regulation, and systemic metabolism. Commensal bacteria modulate epithelial NRP1 expression via Toll-like receptor 2 and Hedgehog signalling, a pathway central to epithelial proliferation, vascular development, and barrier integrity. NRP1 further regulates immune tolerance through its actions on regulatory T cells and shapes macrophage-driven lipid handling and inflammation in adipose tissue, positioning it at the intersection of microbial, immune, and metabolic homeostasis. This review synthesizes current evidence on the molecular and functional biology of NRP1, its regulation by gut microbial signals, and its integrated role across the intestinal barrier, immune, and metabolic axis, alongside the consequences of its dysregulation in disease. We also examine microbiome-directed therapeutic strategies, including fecal microbiota transplantation and probiotic-based approaches, and their variable efficacy across gastrointestinal and metabolic conditions. Despite growing mechanistic insight, the cell-specific functions of NRP1, the directionality of its relationship with microbiota composition, and its translational relevance to human disease remain incompletely defined. Multi-omics and single-cell approaches, alongside causal animal models, are identified as key next steps to determine whether NRP1 represents a disease biomarker or a viable therapeutic target in obesity, type 2 diabetes, and related metabolic disorders.