Essential Role of IFN-γ in Regulating Gut Antimicrobial Peptides and Microbiota to Protect Against Alcohol-Induced Bacterial Translocation and Hepatic Inflammation in Mice.

摘要: 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 pathogenesis ALD. was set to determine how inhibits ability intestinal cells (IECs) and explore possible solutions this issue. C57BL/6J mice were fed either or isocaloric dextrin liquid diet for 8 weeks, IFN-γ-signal transducer activator transcription (STAT) signaling analyzed. We found chronic exposure led a significant reduction IFN-γ levels compared control; protein phosphorylated STAT1 (p-STAT1) p-STAT3 both declined alcohol. then tested effects IFN-γ-STAT on regulating peptides (AMPs), microbiota, progression ALD mouse model feeding, time-course acute treatment, vivo vitro IEC-specific STAT3 knockout models, respectively. Administration activated STAT3, upregulated expression Reg3 α-defensins, orchestrated reversed alcohol-induced ZO-1 disruption systemic endotoxin elevation as well hepatic inflammation. Meanwhile, treatment time-dependently induced AMP α-defensin activation. dissected roles progress. Lack inhibited IFN-γ-induced α-defensins hindered activation via inactivating matrix metallopeptidase 7 (MMP7), whereas lack IFN-γ-stimulated IEC marker, sodium-hydrogen exchanger 3. Lastly, we interleukin (IL)-18, known inducer, also reduced mice. IL-18 alcohol-fed normalized ameliorated organ damages intestine liver. Taken together, reveals regulation AMPs through STAT3; provides an explanation dysfunction microbial dysbiosis. Therefore, remains promising host defense-enhancing cytokine with unexplored clinical potential therapy.