Abstract
The mechanisms by which alcohol provokes bacterial translocation in the development of alcoholic liver disease (ALD) remain incompletely defined. Our previous study demonstrates that impaired gut epithelial antimicrobial defense is critically involved in the pathogenesis of ALD. The study was set to determine the mechanisms of how alcohol inhibits the antimicrobial ability of intestinal epithelial cells (IECs) and to explore possible solutions to this issue. C57BL/6J mice were fed either alcohol or isocaloric dextrin liquid diet for 8 weeks, and intestinal IFN-γ-signal transducer and activator of transcription (STAT) signaling was analyzed. We found that chronic alcohol exposure led to a significant reduction in intestinal IFN-γ levels compared to a control; the protein levels of phosphorylated STAT1 (p-STAT1) and p-STAT3 were both declined by alcohol. We then tested the effects of IFN-γ-STAT signaling on regulating antimicrobial peptides (AMPs), gut microbiota, and disease progression of ALD in a mouse model of chronic alcohol feeding, time-course acute IFN-γ treatment, and in vivo and in vitro IEC-specific STAT1 or STAT3 knockout mouse models, respectively. Administration of IFN-γ activated intestinal STAT1 and STAT3, upregulated the expression of Reg3 and α-defensins, orchestrated gut microbiota, and reversed alcohol-induced intestinal ZO-1 disruption and systemic endotoxin elevation as well as hepatic inflammation. Meanwhile, acute IFN-γ treatment time-dependently induced AMP expression and α-defensin activation. We then dissected the roles of STAT1 and STAT3 in this progress. Lack of IEC-specific STAT3 inhibited IFN-γ-induced expression of Reg3 and α-defensins and hindered activation of α-defensins via inactivating matrix metallopeptidase 7 (MMP7), whereas lack of IEC-specific STAT1 impaired IFN-γ-stimulated expression of α-defensins and the IEC marker, sodium-hydrogen exchanger 3. Lastly, we found that interleukin (IL)-18, a known IFN-γ inducer, was also reduced by alcohol in mice. IL-18 treatment to alcohol-fed mice normalized gut IFN-γ levels and ameliorated organ damages in both the intestine and liver. Taken together, the study reveals that IFN-γ is critically involved in the regulation of AMPs through regulation of STAT1 and STAT3; impaired IFN-γ-STAT signaling provides an explanation for alcohol-induced gut antimicrobial dysfunction and microbial dysbiosis. Therefore, IFN-γ remains a promising host defense-enhancing cytokine with unexplored clinical potential in ALD therapy.
Highlights
Alcoholicliver disease (ALD) is one of the leading causes of chronic liver disease, which encompasses a spectrum of liver pathologies ranging from steatosis, hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (Gao and Bataller, 2011; Bajaj, 2019)
We explored if IFN-γ is involved in alcoholinduced antimicrobial peptides (AMPs) reduction using a mouse model of ALD
IL-18 Treatment Restores Intestinal IFN-γ Levels and Ameliorates Alcohol-Induced Liver Damage. It was not fully understood how alcohol intoxication leads to suppressed intestinal IFN-γ production, so we explored the levels of IFN-γ inducing factor after chronic alcohol feeding and the effects of IL-18 in restoring intestinal IFN-γ levels as well as in reversing the pathogenesis of ALD
Summary
Alcoholicliver disease (ALD) is one of the leading causes of chronic liver disease, which encompasses a spectrum of liver pathologies ranging from steatosis, hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (Gao and Bataller, 2011; Bajaj, 2019). Alcohol consumption leads to disrupted gut barrier as well as intestinal bacterial overgrowth and enteric dysbiosis. These factors contribute to the increased translocation of microbial products, namely pathogen associated molecular patterns (PAMPs), to the liver and subsequent alcohol-related damage (Yan et al, 2011; Bull-Otterson et al, 2013; Zhong et al, 2019). One well-known PAMP is lipopolysaccharide (LPS), levels of which have been shown to correlate with the severity of liver damage in patients with alcoholic hepatitis (Hanck et al, 1998; Parlesak et al, 2000). Mice deficient in LPS receptor Toll-like receptor 4 (TLR4), CD14, or downstream signaling molecule, MyD88, are resistant to ALD (Uesugi et al, 2001; Yin et al, 2001; Hritz et al, 2008)
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