Pro-inflammatory Cytokines Alter Colonocyte Butyrate Metabolism via p38 Signaling Pathway

In ulcerative colitis (UC) and colorectal cancer (CRC), the colonocyte undergoes a metabolic shift. This metabolic shift involves a decrease in the oxidation of the microbial‐derived short‐chain fatty acid, butyrate. The factors that promote this metabolic shift in these diseases are not fully understood. Previously, we showed interleukin‐1β (IL‐1β), a pro‐inflammatory cytokine that is elevated in UC and CRC, decreased the oxidation of butyrate in CRC cells. Experiments identified p38, a mitogen‐activated protein kinase, mediates the diminished butyrate oxidation caused by IL‐1β. We have identified tumor necrosis factor a (TNF‐a) as another pro‐inflammatory cytokine that decreases butyrate oxidation in colorectal cells. The hypothesis is that IL‐1β or TNF‐a drives metabolic shifts in colonocytes that promote disease via the p38 signaling pathway. Both IL‐1β and TNF‐a activate p38 (phosphorylation of p38) in colorectal cancer cells. Next, we utilized the Seahorse XF 24 Analyzer to measure butyrate oxidation with and without IL‐1β or TNF‐a treatment. The oxidation of butyrate was lower in cells treated with IL‐1β or TNF‐a compared to untreated controls. Furthermore, IL‐1β or TNF‐a showed a shift in metabolism from oxidative phosphorylation (OXPHOS) to glycolysis. CRC cells treated with IL‐1β or TNF‐a showed increased extracellular acidification rate compared to controls, which indicates that IL‐1β or TNF‐a induces a switch toward glycolysis. Inhibition of p38 or knockdown of p38 decreased IL‐1β or TNF‐a ability to suppress butyrate oxidation. These data provide a mechanism by which cytokines, through p38, regulate metabolism in the diseased colonocyte. Support or Funding Information USDA R011770176