ROLE OF IMPAIRED INTESTINAL IFN GAMMA SIGNALING IN ALCOHOL-INDUCED BACTERIAL TRANSLOCATION AND LIVER INJURY IN MICE

Alcoholic liver disease (ALD) is associated with bacterial translocation which impacts disease progression. Our previous study found that impaired host antimicrobial defense is critically involved in the pathogenesis of ALD. The present study was set to determine how alcohol inhibits antimicrobial ability and to explore possible solutions to this issue. We analyzed several immune regulatory candidates with the potency of modulating the intestinal antimicrobial function in a mouse model of 8-week alcohol exposure, and found that chronic alcohol exposure led to a significant reduction of intestinal IFN gamma levels, which was coupled with a decline in antimicrobial peptides compared with the control mice. Meanwhile, the protein levels of phosphorylated signal transducer and activator of transcription 1 (p-STAT1) and 3 (p-STAT3) were both reduced in the ileum of mice after alcohol exposure. IFN gamma has been proposed to regulate epithelial homeostasis and control bacterial infection. We then tested the effect of IFN gamma on Paneth cell granule secretion in both WT and intestinal epithelial specific-Stat1 or -Stat3 knockout mice. IFN gamma time-dependently induced alpha defensin secretion from Paneth cells in WT mice, while depletion of STAT1, but not STAT3, in the intestinal epithelial cells abolished the effect. Next, recombinant IFN gamma was given to the alcohol-fed mice through intraperitoneal injection every other day for the last 2 weeks in the 8-week alcohol feeding model. Administration of IFN gamma reversed alcohol-induced p-STAT1 reduction, upregulated the expression of Paneth cell alpha defensins, decreased plasma endotoxin levels, and ameliorated hepatic lipocalin 2 and CXCL1 induction. Lastly, we found that interleukin (IL)-18, a known IFN gamma inducer, was reduced by alcohol in mice. We treated the alcohol-fed mice with IL-18 for the last 2 weeks of alcohol feeding, and found that IL-18 treatment effectively preserved intestinal IFN gamma levels and ameliorated the alcohol-induced liver damage. Taken together, the study reveals that IFN gamma is critically involved in Paneth cell granule release and in controlling bacterial symbiosis through STAT1 signaling. Reverse alcohol-reduced intestinal IFN gamma levels by either IFN gamma or IL-18 treatment could improve host antimicrobial activity, reduce bacterial pathogen translocation, and ameliorate alcohol-induced liver damage.