Abstract
The gut epithelium is a mechanical barrier that protects the host from the luminal microenvironment and interacts with the gut microflora, which influences the development and progression of ulcerative colitis (UC). Licochalcone A (LA) exerts anti-inflammatory effects against UC; however, whether it also regulates both the gut barrier and microbiota during colitis is unknown. The current study was conducted to reveal the regulatory effects of LA on the intestinal epithelium and gut microflora in C57BL/6 mice subjected to dextran sodium sulfate (DSS). Sulfasalazine (SASP) was used as the positive control. Results of clinical symptoms evaluation, hematoxylin, and eosin (H&E) staining, and enzyme-linked immunosorbent (ELISA) assays showed that LA significantly inhibited DSS-induced weight loss, disease activity index (DAI) increase, histological damage, and gut inflammation. Additionally, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and immunohistochemical (IHC) analysis showed that LA maintained the integrity of the intestinal barrier by suppressing cell apoptosis and preserving the expression of tight junction (TJ) proteins. Notably, the optimal dose of LA for gut barrier preservation was low, while that for anti-inflammatory effects was high, indicating that LA might preserve gut barrier integrity via direct effects on the epithelial cells (ECs) and TJ proteins. Furthermore, 16S rRNA analysis suggested that the regulatory effect of LA on the gut microbiota differed distinctly according to dose. Correlation analysis indicated that a low dose of LA significantly modulated the intestinal barrier-associated bacteria as compared with a moderate or high dose of LA. Western blot (WB) analysis indicated that LA exhibited anti-UC activity partly by blocking the mitogen-activated protein kinase (MAPK) pathway. Our results further elucidate the pharmacological activity of LA against UC and will provide valuable information for future studies regarding on the regulatory effects of LA on enteric diseases.
Highlights
As a major inflammatory disease, ulcerative colitis (UC) has been gaining increasing attention worldwide in recent years [1]
Once the gut barrier is disrupted, which is represented by changes in tight junction (TJ) proteins that include claudin-1, occludin, and ZO-1, and an increase in epithelial cells (ECs) apoptosis [8,10], luminal antigens and toxins are able to penetrate the underlying tissue, and the consequent exposure thereof to the luminal antigens induces an inflammatory response and the release of inflammatory cytokines, which trigger further degradation of TJs [11]
The body weight of healthy control mice (CON group) showed a steady increase over the course of the 14 days, while that of dextran sodium sulfate (DSS)-subjected mice increased to a lesser extent throughout the first 9 days but began to decline at day 10
Summary
As a major inflammatory disease, ulcerative colitis (UC) has been gaining increasing attention worldwide in recent years [1]. Despite the efficacy of several types of anti-UC drugs, there still exists an unsatisfactory curative effect, high recurrence, and potential side effects, including allergic reactions, anti-antibody reactions, and infection [2,3,4,5]. It is of major importance and urgency to discover novel anti-UC drugs with higher safety and efficacy rates. Novel drugs that treat or target other aspects of the disease are needed Among these multiple factors involved in UC, gut barrier damage has been identified as a vital etiological factor in colitis [7,8]. Exploiting drugs that synergize gut barrier protection and microbiota regulation could be a promising avenue for UC treatment
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