Macrophage-Orchestrated Metabolic Sensing Drives IBD Pathogenesis: A Framework for Targeted Therapy.

Inflammatory bowel disease (IBD) arises from dysregulated interactions among the gut microbiota, immune system, and intestinal epithelium. Intestinal macrophages are central to these processes, yet are often viewed primarily as downstream inflammatory effectors. Here, we present a conceptual review that reframes intestinal macrophages as metabolic sensors and regulatory hubs that orchestrate inflammatory persistence or resolution. We propose a Macrophage-Orchestrated Metabolic Sensor (MOMS) framework organized into three coordinated layers: Sense, in which macrophages detect microbial- and host-derived metabolites; Switch, in which metabolic and epigenetic reprogramming stabilizes intracellular inflammatory or reparative states; and Command, in which these stabilized states drive epithelial repair, immune-cell recruitment, or fibrotic remodeling. Integrating evidence from immunometabolism, microbiome research, and single-cell biology, we identify key molecular nodes-including METTL3 and NLRP3-as programmable regulators of macrophage fate. The MOMS framework generates testable predictions linking macrophage metabolic states to disease severity and treatment responsiveness, and provides a conceptual foundation for precision macrophage-directed therapies in IBD and related immune-metabolic disorders.