Dipotassium Glycyrrhizate Improves Intestinal Mucosal Healing by Modulating Extracellular Matrix Remodeling Genes and Restoring Epithelial Barrier Functions.

Eleonora Colantoni,Laura Stronati,Roberta Vitali,Vincenzo Cesi,Francesca Palone,Sara Isoldi,Anna Negroni,Salvatore Cucchiara,Anna Barbara Mancuso

doi:10.3389/fimmu.2019.00939

Abstract

Gut mucosal healing (MH) is considered a key therapeutic target and prognostic parameter in the management of inflammatory bowel disease (IBD). The dipotassium glycyrrhizate (DPG), a salt of the glycoconjugated triterpene glycyrrhizin, has been shown to inhibit the High Mobility Group Box 1 (HMGB1) protein, an allarmin strongly implicated in the pathogenesis of most inflammatory and auto-immune disorders. Here we discuss new insights on how DPG acts on MH comparing the acute phase and the recovery phase from experimental colitis in mice. We found that DPG strongly accelerates MH by differently regulating pro-inflammatory (CXCL1, CXCL3, CXCL5, PTGS2, IL-1β, IL-6, CCL12, CCL7) and wound healing (COL3A1, MMP9, VTN, PLAUR, SERPINE, CSF3, FGF2, FGF7, PLAT, TIMP1) genes as observed only during the recovery phase of colitis. Relevant issue is the identification of extracellular matrix (ECM) remodeling genes, VTN, and PLAUR, as crucial genes to achieve MH during DPG treatment. Furthermore, a noticeable recovery of intestinal epithelial barrier structural organization, wound repair ability, and functionality is observed in two human colorectal adenocarcinoma cell lines exposed to DPG during inflammation. Thus, our study identifies DPG as a potent tool for controlling intestinal inflammation and improving MH.

Highlights

Inflammatory bowel diseases (IBD), are complex disorders of the gastrointestinal (GI) tract whose major phenotypes are Crohn’s disease (CD), and ulcerative colitis (UC)
Recovery After DSS-Induced Colitis Mice, were given 3% DSS in drinking water for 5 days followed by 9 days of regular water or 8 mg/kg/day dipotassium glycyrrhizate (DPG), administered by oral gavage; mice were divided into the following groups (5 animals per group): [1] mice treated with DSS for 5 days and sacrificed; [2] mice treated with DSS for 5 days, DSS was removed and animals were treated with a vehicle (PBS) at 6, 24, 72, 144, 216 hours and sacrificed; [3] mice treated with DSS for 5 days, DSS was removed and animals were treated with 8 mg/kg/day DPG at 6, 24, 72, 144, 216 hours and sacrificed
C57BL/6 mice were randomly divided into three groups: control group received regular drinking water, mice treated with 3% DSS to induce colitis and mice treated with 3% DSS and 8 mg/kg/day DPG, daily administered by oral gavage

Summary

Introduction

Inflammatory bowel diseases (IBD), are complex disorders of the gastrointestinal (GI) tract whose major phenotypes are Crohn’s disease (CD), and ulcerative colitis (UC). IBD are featured by chronic inflammation which may result in irreversible mucosal damage, disability, and heightened incidence of colitis-associated neoplasias [1, 2]. Recent studies have identified gut mucosal healing (MH) as key therapeutic target and prognostic parameter in the management of IBD. The structural basis of MH is the restitution of gut epithelium that prevents translocation of commensal bacteria into the mucosa and subsequent immune-stimulation [6, 7]. Achieving MH prompts better long-term results, such as less hospitalization and surgery as well as better quality of life, with a critical impact on the natural history of the disease [8]

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