Phosphocreatine Rescues Intestinal Epithelial Metabolic Dysfunction Related to Creatine Kinase Loss and Is Protective in Murine Colitis.

Background & Aims: Inflammatory bowel disease is associated with intestinal energetic derangements, including reduced creatine kinase (CK) expression. CK is critical to cellular energetics, catalyzing bidirectional transfer of high-energy phosphate between creatine and ATP, and phosphocreatine (PCr) and ADP. However, the impact of CK loss on intestinal epithelial cells (IECs) remains unclear. We aimed to characterize energetic and functional consequences of CK deficiency in IECs and identify a treatment to circumvent CK loss.

Methods: The CK-brain isoform was knocked down (CKB KD) in T84 cells. Colonoids were derived from CK-brain/mitochondrial isoform knockout (CK dKO) mice. Cell lines were characterized by quantitative polymerase chain reaction, immunoblot, high-performance liquid chromatograph, Seahorse assays, transepithelial electrical resistance, wound healing, immunofluorescence, and proliferation assays, and in the presence of supplemental PCr. CK dKO mice treated with PCr in the setting of colitis were evaluated by clinical and histologic disease scoring.

Results: CKB KD T84s and CK dKO colonoids demonstrated signs of energy deficiency, including reduced ATP levels and oxidative phosphorylation capacity. This was associated with diminished IEC function, most notably proliferation, and impaired barrier formation and scratch-wound healing. Supplementing PCr normalized ATP levels, proliferation, and barrier formation. Oral PCr supplementation during murine colitis resulted in improved disease activity.

Conclusions: Loss of CK, a change that occurs in inflammatory bowel disease, causes defective energy metabolism and IEC functioning. PCr supplementation rescues many detrimental effects of CK loss and serves as a protective mechanism in murine colitis. These findings may provide insight into pathogenic mechanisms and a novel therapeutic modality in inflammatory bowel disease.