IgY antibodies against cytolysin reduce ethanol-induced liver disease in mice

Abstract

Background and Aims: Patients with severe alcohol-associated hepatitis have high morbidity and mortality. Novel therapeutic approaches are urgently needed. The 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 the presence of fecal cytolysin-positive E. faecalis predicted 180-day mortality in those patients. After combining this smaller cohort with our previously published multicenter cohort, the 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. The oral administration of IgY antibodies against cytolysin decreased ethanol-induced liver disease in gnotobiotic mice colonized with stool from cytolysin-positive patients with alcoholassociated hepatitis.

Fungal signature differentiates alcohol-associated liver disease from nonalcoholic fatty liver disease

“…To identify fungal genera and species with the highest feature importance for detecting ALD vs NAFLD, we determined the mean decrease accuracy per random forest analysis, as described before. 32 , 33 Among the top genera differentiating ALD from NAFLD were Scopularopsis , Kluyveromyces , unidentified genera, Mucor , Saccharomyces , and Kazachstania ( Figure 2a ). Among the fungal species with the highest feature importance for detecting ALD vs NAFLD were S. cordiae , M. restricta , unknown species, S. cerevisiae , and C. albicans ( Figure 2b ).…”

“… 31 Area under the curve (AUC), best threshold to maximize the Youden index, sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and p value between two AUCs of receiver operating characteristic (ROC) curves per DeLong method were calculated using the pROC library in R; and to identify fungal genera and species with the highest feature importance for detecting ALD cohorts vs NAFLD cohorts, the mean decrease accuracy was calculated with the randomForest library in R, as described. 32 , 33 Statistical analysis was performed using R statistical software, R version 1.3.1093 for Mac, 2020 the R Foundation for Statistical Computing.…”

The role of the microbiome in liver disease

“…The abundance of fecal cytolysin-positive E. faecalis correlates with the severity of liver disease in patients with alcohol-associated hepatitis. Bacteriophages targeting cytolytic E. faecalis as well as IgY antibody administration against cytolysin attenuate experimental ethanol-induced liver disease [46,47]. Fecal cytolysin did not predict disease severity in patients with liver cirrhosis and acute decompensation and in patients with acute on chronic liver FIGURE 2.…”

Development of a Quantitative PCR Method for Detecting Enterococcus faecalis Cytolysin in Human Stool Samples

“…2023, 6, 107 2 of 12 recently emerged as compelling candidates with potential clinical implications [9]. Recent studies [9,10] observed an increased relative abundance of E. faecalis in the feces from patients with alcohol-associated hepatitis, specifically a strain that secretes the exotoxin cytolysin. The presence of cytolysin-positive E. faecalis correlated with the severity of liver disease and mortality rate in patients with alcohol-associated hepatitis [9].…”