Abstract
Background: The progression of liver disorders is frequently associated with inflammatory bowel disease through the gut-liver axis. However, no direct evidence showed the mechanisms of ulcerative colitis (UC) in the development of liver fibrosis per se. Thus, this study aimed to evaluate the effects of UC on liver fibrosis and its potential mechanism in the experimental model.Methods: Male C57BL/6 mice were allocated into five groups (n = 10 per group) to receive either drinking water (control), 2% dextran sulfate sodium (DSS), olive oil, carbon tetrachloride (CCl4) or DSS + CCl4 for 4 cycles. Blood was collected for biochemical analysis. Colons were excised for the evaluation of colon length and morphological score. Liver, colon, and mesenteric lymph nodes (MLNs) were collected for histopathological staining, expression analysis, and bacterial translocation assay to evaluate the inflammation, fibrosis, the activation of hepatic stellate cells (HSCs), and gut barrier function.Results: DSS caused severe colitis in mice treated or treated with CCl4, as evident from the elevation of disease activity index (DAI), histological abnormalities, and increased pro-inflammatory cytokines (TNF-α, IFN-γ, and IL-17A). Histopathological staining revealed that DSS treatment aggravated the CCl4-induced extracellular matrix deposition, liver fibrosis, and inflammation in mice. Additionally, biochemical and expression analysis indicated the DSS treatment caused the increase of hydroxyproline and pro-inflammatory cytokines, as well as the abnormal liver function indexes in CCl4-induced mice. Gut barrier function was impaired in DSS- and DSS + CCl4-treated mice, manifesting as the increase in bacterial translocation and lipopolysaccharide level, and the reduction in tight junction proteins (occluding, claudin-1 and ZO-1) expression. Further, the activations of HSCs and TLR4 signaling pathway were observed after DSS + CCl4 treatment, presenting with the increase in expression of α-SMA, vimentin, TGF-β, collagen type I, collagen type II, TIMP-2, TLR4, TRAF6, and NF-κB p65, and a decrease in GFAP and MMP-2 expression.Conclusion: The present study verified that UC aggravated CCl4-induced liver injury, inflammation, and fibrosis in mice through the gut-liver axis. Gut barrier dysfunction in UC leads to bacterial translocation and elevated lipopolysaccharide, which may promote the activation of TLR4 signaling and HSCs in the liver.
Highlights
Liver fibrosis is a common disease associated with various liver disorders such as viral hepatitis, and alcoholic liver, which often leads to gradual loss of liver function (Shiha et al, 2017)
The study of the mechanism indicated that altered intestinal permeability presented as down-regulation of tight junction proteins in colitis mice may favor the passage of bacterial products such bacterial LPS into the liver through the portal vein, and increased LPS activated TLR4 signaling and HSCs activation which involved in liver inflammation and fibrogenesis (Figure 6)
The present study provided the first direct evidence for the pathogenesis of CCl4-induced liver fibrosis
Summary
Liver fibrosis is a common disease associated with various liver disorders such as viral hepatitis, and alcoholic liver, which often leads to gradual loss of liver function (Shiha et al, 2017). It has the potential to progress into cirrhosis, even liver cancer, and liver failure if not necessarily prevented (Aydın and Akçalı, 2018). The progression of fibrosis, and cirrhosis, is responsible for significant morbidity and mortality (Berumen et al, 2021). Despite numerous therapeutic targets have been identified in liver fibrosis, no clinical trial has so far provided unequivocal evidence for a complete reversal of cirrhosis (Povero et al, 2010; Pellicoro et al, 2014). Identifying the critical pathways and mechanisms in liver fibrosis is likely to provide novel insights for clinical translation. The progression of liver disorders is frequently associated with inflammatory bowel disease through the gut-liver axis. No direct evidence showed the mechanisms of ulcerative colitis (UC) in the development of liver fibrosis per se. This study aimed to evaluate the effects of UC on liver fibrosis and its potential mechanism in the experimental model
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