Abstract
Empagliflozin and metformin are widely used for the treatment of type 2 diabetes. These drugs showed marked anti-inflammatory effects in different animal models via enhancing AMPK activity. Yet, the protective anti-inflammatory effects of their combination against ulcerative colitis have not been previously investigated. The current study aimed to explore the potential of empagliflozin/metformin combination to mitigate the DSS-induced rat colitis model. The modulating effects of empagliflozin and metformin on the AMPK/mTOR/NLRP3 axis and T cell polarization were delineated. In this study, distal colons were examined for macroscopic and microscopic pathological alterations. ELISA, qRT-PCR, and immunohistochemistry techniques were applied to detect proteins and cytokines involved in AMPK/mTOR/NLRP3 axis and T Cell polarization. Oral administration of empagliflozin (10 mg/kg/day) and metformin (200 mg/kg/day) combination alleviated colitis as revealed by the reduced disease activity index, macroscopic damage index, colon weight/length ratio, and histopathologic scoring values. Interestingly, empagliflozin/metformin combination significantly enhanced AMPK phosphorylation and depressed mTOR and NLRP3 expression leading to a subsequent reduction in caspase-1 cleavage and inhibition of several inflammatory cytokines, including IL-1β, and IL-18. Reduced mTOR expression and reduced IL-6 levels led to a reduction in Th17 cell polarization and maintenance. Together, the current study reveals that the protective effects of empagliflozin and metformin against DSS-induced colitis are fundamentally mediated via enhancing AMPK phosphorylation. Since adult humans with diabetes mellitus are at greater risk for developing inflammatory bowel diseases, clinical application of empagliflozin/metformin combination represents a novel therapeutic approach for treating diabetic patients with ulcerative colitis.
Highlights
Ulcerative colitis is a chronic inflammatory bowel disease that is marked by increased intestinal motility and bloody diarrhea
In regard to the previous literature, our study aimed to examine the anti-inflammatory effect of adenosine monophosphateactivated protein kinase (AMPK) activation by oral administration of empagliflozin or metformin in dextran sulfate sodium (DSS)-induced ulcerative colitis in rats
The colon weight/length ratio was elevated in the DSS group compared with control groups or ulcerative groups treated with empagliflozin or metformin or their combination (Figure 1A)
Summary
Ulcerative colitis is a chronic inflammatory bowel disease that is marked by increased intestinal motility and bloody diarrhea. The clinical value of existing therapeutic strategies of ulcerative colitis, including glucocorticoids, anti-tumor necrosis factor α (TNF-α), mesalamine, and thiopurines is still limited. Adenosine monophosphate (AMP)activated protein kinase (AMPK) is a conserved fuel-sensing enzyme that plays an important role in the regulation of cellular metabolism where it increases glucose and fatty acids uptake and activates the oxidation process to improve the cellular energy utilization (Marin-Aguilar et al, 2017). AMPK activation is believed to counter many cellular disturbances such as inflammation, insulin resistance, and abnormal fat deposition (Ruderman et al, 2013). The diminished activity of AMPK and its failure to restore normal cellular energy levels is associated with these metabolic abnormalities and predisposed inflammation and apoptosis (Wu and Zou, 2020)
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