Figure 2: Extending the M1/M2 paradigm to colonocytes.

(A and B) Cytokine signaling can polarize macrophage metabolism and function, a process that is reversible. (A) Interleukin (IL)-4 and IL-13 stimulate polarization into alternatively-activated M2 macrophages by inducing STAT6 signaling to drive a PPARγ-dependent activation of mitochondrial β-oxidation and concomitant repression of the Nos2 gene. (B) Pro-inflammatory signals, such as gamma interferon (IFN-γ), stimulate polarization into classically-activated M1 macrophages by shifting the host cell metabolism towards anaerobic glycolysis. (C) The microbiota converts fiber into fermentation products, such as butyrate, which stimulates a metabolic polarization into homeostatically-activated C2 colonocytes by inducing a PPARγ-dependent activation of mitochondrial β-oxidation, thereby lowering epithelial oxygenation. (D) Pro-inflammatory signals stimulate a metabolic polarization into C1 colonocytes by shifting the host cell metabolism towards anaerobic glycolysis, thereby increasing epithelial oxygenation, which results in oxygen (O₂) emanating from the epithelial surface. Lactate produced during anaerobic glycolysis is released into the gut lumen, whereas nitric oxide (NO) produced by iNOS is converted to nitrate (NO₃⁻). CO₂, carbon dioxide.