LAUSR

BACKGROUND Patients with severe alcohol-associated hepatitis have a high morbidity and mortality. Novel therapeutic approaches are urgently needed. Aims of our study were to confirm the predictive value of cytolysin-positive Enterococcus faecalis (E. faecalis) for mortality in patients with alcohol-associated hepatitis and to assess the protective effect of specific chicken immunoglobulin Y (IgY) antibodies against cytolysin in vitro and in a microbiota humanized mouse model of ethanol-induced liver disease. APPROACH AND RESULTS We investigated a multicenter cohort of 26 subjects with alcohol-associated hepatitis and confirmed our previous findings that presence of fecal cytolysin-positive Enterococcus faecalis predicted 180-day mortality in those patients. After combining this smaller cohort with our previously published multicenter cohort, presence of fecal cytolysin has a better diagnostic area under the curve, better other accuracy measures, and a higher odds ratio to predict death in patients with alcohol-associated hepatitis than other commonly used liver disease models. In a precision medicine approach, we generated IgY antibodies against cytolysin from hyperimmunized chickens. Neutralizing IgY antibodies against cytolysin reduced cytolysin-induced cell death in primary mouse hepatocytes. Oral administration of IgY antibodies against cytolysin decreased ethanol-induced liver disease in gnotobiotic mice colonized with stool from cytolysin-positive patients with alcohol-associated hepatitis. CONCLUSION E. faecalis cytolysin is an important mortality predictor in alcohol-associated hepatitis patients and its targeted neutralization via specific antibodies improves ethanol-induced liver disease in microbiota humanized mice.