Immunometabolism as a New Bimodal Therapeutic Concept in Inflammatory Bowel Disease and Immune-Mediated Inflammatory Disorders

Immunometabolism exerts a bimodal action at the interface of extracellular immune response and intracellular metabolism, putting it at the center of many immune-mediated inflammatory disorders (IMIDs). Research has shown that immunometabolic pathways may act as a dual checkpoint for the inflammatory cycle to return the system to homeostasis by inactivating inflammatory pathways and shifting metabolism in favor of regulatory phenotypes. In addition, immunometabolic targets may act in non-immune cells such as epithelial and mesenchymal cells. Therefore, the therapeutic approach to targeting the uniquely robust mechanisms of immunometabolism may ameliorate aspects of IMIDs that remained to be addressed. Several emerging targets, including mitochondrial regulators (eg NLRX1), membrane-bound receptors (eg PLXDC2), and hormonal peptides (eg GLP-1), illustrate the diverse ways immunometabolism can be leveraged therapeutically. Preclinical models of inflammatory bowel disease (IBD) and other IMIDs have highlighted the bimodal immunoregulatory roles of these pathways. Preliminary clinical data support the potential utility of immunometabolic modulation, particularly in combination with existing therapies, to overcome the current therapeutic ceiling in clinical efficacy. Continued research is needed to validate the efficacy, safety, and mechanistic precision of immunometabolic agents across the spectrum of IMIDs.