Creatine maintains intestinal homeostatsis and protects against colitis

Turer et al. Proc. Natl. Acad. Sci. USA. 2017. 114: E1273-E1281

Speaker: Yi-Shiang Wang (王奕翔)              Time: 13:10-1400, Apr. 19, 2017

Commentator: Chih-Peng Chang (張志鵬老師)          Place: Room 601

Abstract:

Ulcerative colitis and Crohn’s disease, collectively known as inflammatory bowel disease (IBD), are caused by the perturbation of the balance between the ability to respond to pathogens and tolerance to normal commensal bacteria in the intestinal tract. The integrity of intestinal mucosal barrier is essential for maintaining the balance. Creatine, a nitrogenous acid, functions in the replenishment of cytoplasmic ATP via the phosphocreatine shuttle¹. In human body, creatine is provided equally by the diet and endogenous synthesis. Deficiency in creatine biosynthesis causes diseases, such as neurological disorder¹. In this study, the authors carried out a forward genetic screen of N-ethyl-N-nitrosourea (ENU)-induced mutant mice exposed to dextran sodium sulfate (DSS), which can damage intestinal mucosa and induce colitis in mice, to identify genes involved in intestinal homeostasis². They screened 36,530 third-generation germline mutant mice and identified 27 colitis susceptibility phenotypes. Among them, one mutant (Gatm^mb/mb) was correlated with a point mutation in Gatm (glycine-amidinotransferase, mitochondrial), which encodes glycine amidinotransferase (GATM) that catalyzes the rate-limiting step of creatine biosynthesis, in a recessive model of inheritance. The Gatm^mb/mb mice exhibited colitis symptoms following DSS treatment, which could be reversed by creatine supplementation. Furthermore, Gatm knockout (Gatm^c/c) mice generated by the CRISPR/Cas9-mediated targeting also had the colitis phenotype, thus establishing the causal relationship of Gatm to colitis. The colonic epithelium of Gatm^c/c mice displayed increased cell death and decreased proliferation, as well as increased metabolic stress in response to DSS with higher levels of phospho-AMPK and lower levels of phospho-mTOR during DSS treatment. In conclusion, identification of the mutation in Gatm demonstrates that abnormal cellular energy metabolism can promote the induction of colitis.

References:

1.     Joncquel-Chevalier Curt M et al. Creatine biosynthesis and transport in health and disease. Biochimie 2015, 119: 146-165.

2.     Justice MJ et al. Mouse ENU mutagenesis. Hum. Mol. Genet. 1999, 8: 1955-1963.