Macrophage Metabolic Reprogramming in Inflammatory Bowel Diseases: From Pathogenesis to Therapy

Abstract

Inflammatory bowel disease (IBD), encompassing two subtypes, ulcerative colitis, and Crohn's disease, is a chronic, non-specific gastrointestinal disorder with a complex etiology stemming from various factors. The incidence of IBD has been steadily rising in the past few years, causing great physical and mental strain on patients. Traditional IBD therapeutic drugs include anti-inflammatory drugs, immunosuppressants, and biologics; however, they may have serious adverse effects. This has fueled active clinical research exploring new targets for IBD treatment, focusing on the unique metabolic pathways and functions of macrophages. Macrophage immune metabolism plays a crucial role in IBD; however, the mechanism is unclear. This review discussed the role and potential mechanisms of macrophage metabolic reprogramming in IBD and the link between macrophages and ferroptosis. While these findings from preclinical models suggest novel therapeutic avenues for IBD, such as targeting macrophage metabolic reprogramming and hypothetical approaches like ferroptosis modulation, their clinical applicability remains speculative; rigorous disease-specific validation is imperative.

Keywords: inflammatory bowel diseases; macrophage; metabolic reprogramming; pathogenesis; therapy.

Figure 1

Macrophage glucose metabolism in IBD. During inflammatory bowel disease (IBD), macrophages shift from oxidative phosphorylation to glycolytic metabolism. In the mitochondria, the tricarboxylic acid cycle presents two break points, resulting in the accumulation of citrate and succinate. Citrate can be transported to the cytoplasm via the SLC25a1 transporter on the mitochondrial membrane to produce reactive oxygen species (ROS), nitric oxide, and Prostaglandins. Succinate activates HIF-1α. Succinate can bind to SUCNR1 on the cell membrane and increase IL-1β.

Figure 2

Macrophage lipid metabolism in IBD. Downregulation of PPAR-γ expression leads to reduced fatty acid oxidation during IBD. Citrate can be transported to the cytoplasm via the SLC25a1 transporter on the mitochondrial membrane to generate Fatty acids in response to FASN, resulting in increased fatty acid synthase.

Figure 3

Macrophage ferroptosis in IBD. Fe3+ binds to transferrin and is transported to the cell through TfR1, where it is reduced to Fe2+, which is partially stored in the labile iron pool. Excessive intracellular accumulation of Fe3+ and Fe2+ can cause the Fenton reaction, which produces ROS and eventually leads to ferroptosis.