Immunometabolic alterations in the gut can lead to intestinal inflammatory diseases such as inflammatory bowel disease (IBD). Sokol and colleagues show that the microorganism-derived polyamine cadaverine acts in a concentration- and context-specific manner to direct monocyte and macrophage metabolism towards either glycolysis or oxidative phosphorylation, thereby promoting either pro- or anti-inflammatory polarizations, respectively. Under baseline conditions, cadaverine enters macrophages via l-lysine transporters and activates the thioredoxin system, whereas under inflammatory conditions, it activates aconitate decarboxylase and upregulates itaconate. Both pathways induce the transcription factor NRF2 and anti-inflammatory polarization. However, at high levels, cadaverine also binds the histamine 4 receptor and induces pro-inflammatory functions. Levels of cadaverine are mainly controlled by Enterobacteriaceae, and in mice with experimental colitis and an antibiotic-depleted microbiome, treatment with an optimum level of oral cadaverine protected them from disease, whereas higher cadaverine levels exacerbated disease. These findings may be of therapeutic relevance, given that increased levels of cadaverine are associated with an enhanced flare risk in individuals with IBD.