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

Abstract

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.

Activating AMPK to Restore Tight Junction Assembly in Intestinal Epithelium and to Attenuate Experimental Colitis by Metformin

“…For example, activated macrophages and T-helper 17 cell have increased glucose uptake and glycolysis; conversely, anti-inflammatory cells, such as M2 macrophages, regulatory T cells, have lower glycolytic rates and higher levels of oxidative metabolism. AMPK activation creates a pseudo-starving state that can promote oxidative metabolism and inhibits inflammation through many signaling networks, such as nuclear factor κB and mitogen-activated protein kinases (MAPK) signaling pathway ( O’Neill and Hardie, 2013 ; Song et al, 2015 ; Peixoto et al, 2017 ; Di Fusco et al, 2018 ). Hence, AMPK is a crucial regulator of these metabolic dysfunction responses in immune cells.…”

AMPK in regulation of apical junctions and barrier function of intestinal epithelium

“…26,96 Inflammation directly disrupts the assembly of apical junctions and thus increases epithelial permeability. 97 In addition, inflammation activates Wingless and Int (Wnt)/β-catenin signaling, which promotes epithelial proliferation but inhibits differentiation, thus impairing epithelial barrier formation. 96,98 AMPK activation triggers cell cycle arrest, 99,100 consistent with the repressive roles of AMPK in epithelial proliferation and promotion of differentiation.…”

Immunomodulatory Effects of Drugs for Effective Cancer Immunotherapy

“…Cha et al have shown that metformin reduces the stability and membrane localization of programmed death-ligand 1 (PD-L1) and contributes to the enhancement of cytotoxic T lymphocyte (CTL) activity against cancer cells [ 28 ]. Metformin also exerts anti-inflammatory effects [ 29 , 30 ]. It was recently reported that these effects might be related to the alteration of gut microbiota [ 31 ].…”