Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation

• DOI: 10.1042/cs20180167
• Publication Date: 2018-03-14T17:50:33Z
• Authors: Davide Di Fusco; Vincenzo Dinallo; Ivan Monteleone; Federica Laudisi; Irene Marafini; Eleonora Franzè; Antonio Di Grazia; Rami Dwairi; Alfredo Colantoni; Angela Ortenzi; Carmine Stolfi; Giovanni Monteleone
• Keywords: Crohn’s disease; 0301 basic medicine; Colon; Settore MED/12 - GASTROENTEROLOGIA; Drug Evaluation, Preclinical; Ulcerative; AMP-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Mice; 03 medical and health sciences; Settore BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA; inflammatory bowel disease; Insulin; Animals; Hypoglycemic Agents; Intestinal Mucosa; Phosphorylation; Inbred BALB C; ulcerative colitis; Mice, Inbred BALB C; Animal; Interleukin-6; Colitis; Preclinical; Metformin; Receptor, Insulin; 3. Good health; Enzyme Activation; Disease Models, Animal; Disease Models; Drug Evaluation; Colitis, Ulcerative; Female; Inflammation Mediators; Receptor

Metformin, a hypoglycemic drug used for treatment of type 2 diabetes, regulates inflammatory pathways. By using several models of intestinal inflammation, we examined whether metformin exerts anti-inflammatory effects and investigated the basic mechanism by which metformin blocks pathologic signals. Colitic mice given metformin exhibited less colonic inflammation and increased expression of active AMP-activated protein kinase, a mediator of the metabolic effects of metformin, in both epithelial and lamina propria compartments. Pharmacological inhibition of AMP-activated protein kinase reduced but did not prevent metformin-induced therapeutic effect as well as treatment of colitic mice with a pharmacological activator of AMP-activated protein kinase attenuated but did not resolve colitis. These data suggest that the anti-inflammatory effect of metformin relies on the control of additional pathways other than AMP-activated protein kinase. Indeed, metformin down-regulated p38 MAP kinase activation in colitic mice through an AMP-activated protein kinase-independent mechanism. Expression of active form of AMP-activated protein kinase was reduced in inflammatory bowel disease patients and treatment of mucosal cells of such patients with metformin enhanced AMP-activated protein kinase activation and reduced p38 MAP kinase activation, thereby inhibiting interleukin-6 expression. Our findings indicate that metformin is a good candidate for inhibiting pathological inflammation in the gut.