Conclusion: DUR-928 was well tolerated at doses tested in AH patients, including severe AH patients. Compared to the healthy subjects, AH patients had a much slower clearance, resulting in a 2- fold higher C max and 6-fold higher AUC. However, the drug exposure was not affected by the severity of the disease. References 1. McClain C. et al., J. Hepatology, 2019; 70(1), S834A 2. Hassanein T. et al., AASLD -2019 – Late Breaker A09 THU085 Alterations and role of bioactive lipid metabolites (oxylipins) in human and experimental ALD: associations with disease severity Jeffrey Warner 1 , Kara Zirnheld 1 , Vatsalya Vatsalya 1 , Dennis Warner 1 , Josiah Hardesty 1 , Craig J. McClain 1 , Irina Kirpich 1 . 1 University of Louisville School of Medicine, Gastroenterology, Hepatology, and Nutrition, Louisville, United States Email: irina.kirpich@louisville.edu Background and Aims: Alcoholic liver disease (ALD) is a major contributor to total liver disease burden worldwide. ALD pathogen- esis is not well understood and there is no effective therapy. Oxylipins, including epoxy- and dihydroxy-fatty acids (Ep-FAs and dihydroxy-FAs, respectively), are important signaling molecules that regulate various biological processes. Evidence suggests Ep-FAs are beneficial, anti-inflammatorylipid mediators, whereas the properties of dihydroxy-FAs are not well determined. In this study we aimed to: i) examine alcohol-induced alterations in plasma oxylipin levels in human ALD and ii) investigate the effects of dihydroxy-FAs in experimental ALD. Method: Human studies: plasma lipidomic analysis was performed on 44 moderate (mAH) and severe (sAH) alcoholic hepatitis patients and 29 socially drinking healthy controls (HC). Animal studies: male C57BL/6 mice were subjected to a chronic-binge animal model of ALD (NIAAA model). Mice were administered either 8,9-DiHETE or a combination of 9,10-DiHOME and 12,13-DiHOME by i.p. injection once daily for two days prior tosacrifice. Liver injury, inflammation, and steatosis were evaluated. Primary mouse hepatocytes were treated with 8,9-DiHETE, 9,10-DiHOME, 12,13-DiHOME and baseline or palmitic acid (PA)-induced cell death was evaluated. Results: Among dihydroxy-FAs, 8,9-DiHETE was elevated in both mAH and sAH compared to HC. 9,10-DiHOME was significantly elevated in mAH but not in sAH, while 12,13-DiHOME was similar in AH patients and HC. 9,10- and 12,13-EpOMEs were significantly decreased in both mAH and sAH compared to HC. Multivariable regression analysis revealed a moderate association between low 12,13-EpOME/high 8,9-DiHETE and plasma cytokeratin 18 M65 (CK18 M65), a marker of necrotic cell death in sAH (r 2 = 0.3333, p = 0.0478). In vivo, 8,9-DiHETE treatment modestly, while 9,10/12,13-DiHOME significantly, increased liver injury in mice as determined by elevated plasma ALT levels. Dihydroxy-FA treatment had minor effects on hepatic inflammation. In vitro, 8,9-DiHETE treatment significantly exacerbated PA-induced cell death of primary mouse hepatocytes, whereas 9,10-DiHOME, and 12,13-DiHOME had no effect on PA- induced or baseline cell death. Conclusion: Plasma lipidomic analysis in human ALD identified distinct alterations of several plasma oxylipins between mAH and sAH. These bioactive lipid mediators mayserve as novel biomarkers of ALD severity and represent therapeutic targets to prevent and/or attenuate progression of ALD. Dihydroxy-FAs, specifically 8,9- DiHETE, exacerbated liver injury in mice and increased PA-induced cell death in primary hepatocytes. Future studies are warranted to dissect the effects of individual dihydroxy-FAs in ALD. THU086 Alcohol-induced liver injury is attenuated by human beta defensin in experimental ALD via improvements in the gut-liver axis Jeffrey Warner 1 , Ida Larsen 2 , Dennis Warner 1 , Josiah Hardesty 1 , Ying Song 1 , Rui Sun 3 , Zhongbin Deng 3 , Peter Nordkild 4 , Craig J. McClain 1 , Benjamin Jensen 2 , Irina Kirpich 1 . 1 University of Louisville School of Medicine, Gastroenterology, Hepatology, and Nutrition, Louisville, United States; 2 Laval University, University Institute of Cardiology and Pulmonology, Quebec City, Canada; 3 University of Louisville School of Medicine, Oncology, Louisville, United States; 4 Defensin Therapeutics ApS, Copenhagen, Denmark Email: irina.kirpich@louisville.edu Background and Aims: Alcohol-induced liver disease (ALD) is associated with altered gut microbiota, compromised intestinal barrier functions, and endotoxemia, which further exacerbate liver damage. Currently, ALD has very limited effective therapeutic options. Defensins are small host peptides with bactericidal/ immunomodulatory functions, which demonstrated beneficial effects in various animal models associated with inflammation. Here, we tested the hypothesis that human beta defensin 2 (hBD2) would attenuate ethanol-induced liver injury via improvement of gut barrier integrity and beneficial changes in the gut microbiome. Methods: Male C57BL/6J mice were chronically fed ethanol (EtOH) for 5 weeks. During the final week, a subset of mice was administered 1.2 mg/kg hBD2 by oral gavage (8 treatments). Liver steatosis, injury and inflammation were evaluated. Pro-inflammatory lymphocytes were analyzed by flow cytometry in the intestine and mesenteric lymph nodes (MLN). Fecal microbiome was determined by 16S sequencing. Mouse intestinal enteroids were established and subjected to IFN-γ ± hBD2 treatment. Results: Compared to EtOH-fed mice, EtOH + hBD2 treated animals revealed reduced hepatic steatosis, less liver damage as demonstrated by a 50% decrease in plasma ALT levels (p < 0.05), and a 60% decrease in the number of TUNEL-positive hepatocytes (p < 0.05). Further, hBD2 treatment reduced hepatic neutrophil numbers by 70% (p < 0.05) with a concomitant decrease in the expression of several proinflammatory genes, including chemoattractant cytokines, Mip2a and Mcp1. MLN-derived lymphocytes showed a decrease in pro- inflammatory Th1 (CD4 + IFNγ + ) and Th17 (CD4 + IL17a + ) cell popula- tions by 55% and 33% respectively in EtOH + hBD2 compared to EtOH- fed mice. Fecal microbiome analysis revealed similar alpha diversity but a significant difference in composition, including increase in Bifidobacterium and decrease in Akkermansia in EtOH+hBD2 com- pared to EtOH treated mice. These changes have previously been linked to protection from and exacerbation of barrier dysfunction, respectively, in other liver disease states. Finally, small intestine enteroids treated with IFN-γ had decreased expression of the tight junction proteins, including Ocln, which was attenuated by co- treatment with hBD2. POSTER PRESENTATIONS S181 Journal of Hepatology 2020 vol. 73 | S123–S400