Peptide YY reduces cytotoxicity of Candida albicans in alcohol-associated liver disease

Transitioning from yeast to hyphal morphology enables Candida albicans (C. albicans) to secrete candidalysin, invade the intestinal mucosa and translocate to the blood stream. Patients with alcohol-associated hepatitis show increased intestinal abundance of C. albicans, and the candidalysin-encoding gene is associated with reduced survival. Paneth cell-derived peptide YY (PC-PYY) inhibits hyphal growth of C. albicans. In this study, we evaluated the potential of different C. albicans strains isolated from patients with alcohol-associated hepatitis to cause systemic infections and explored the therapeutic potential of PC-PYY in ethanol-induced liver disease in mice.

C. albicans strains isolated from fecal samples of patients with alcohol-associated hepatitis (n = 105) were co-cultured with intestinal epithelial Caco-2 cells to assess in vitro cytotoxicity. Caco-2 cells and primary mouse hepatocytes were incubated with C. albicans in the presence or absence of PC-PYY. Mice were subjected to a chronic plus binge ethanol-feeding model.

C. albicans strains isolated from stool of patients with alcohol-associated hepatitis induced significant cytotoxicity in Caco-2 cells, and high cytotoxicity was associated with worse 30-day survival (log-rank p = 0.032). This cytotoxicity was primarily mediated by the hyphal form and largely driven by candidalysin. PC-PYY significantly reduced C. albicans-induced cytotoxicity in Caco-2 cells (Wilcoxon rank-sum test, p = 0.015) and in primary mouse hepatocytes (p = 0.03) compared with a scrambled peptide control, by inhibiting hyphal morphogenesis. The peptide YY-to-chromogranin A ratio in intestinal crypts was significantly increased in ethanol-fed mice compared with both isocaloric (p = 0.005) and antifungal-treated controls (p = 0.009), indicating that fungal overgrowth stimulates PC-PYY release. In ethanol-fed mice, PC-PYY administration attenuated liver injury (p = 0.032) and steatosis (p = 0.0498) and reduced fecal hyphae formation (p = 0.0159).

PYY inhibits filamentous growth of C. albicans in vitro and alleviates ethanol-induced liver disease in mice, highlighting its potential as a therapy for patients with alcohol-associated liver disease.

Candida albicans (C. albicans) and particularly its toxin candidalysin are associated with poor outcomes in patients with alcohol-associated hepatitis but the extent to which the cytotoxicity of individual C. albicans strains influences patient survival, and the role of Paneth cell-derived PYY (PC-PYY) in this context remains elusive. This study identifies a link between the cytotoxic effect of patient-derived C. albicans strains and survival in patients with alcohol-associated hepatitis and demonstrates that PC-PYY plays a protective role in ethanol-induced liver disease by limiting candidalysin-producing hyphae. Our work provides insight into why some patients with alcohol-associated liver disease have worse outcomes and highlights the potential of PC-PYY as a therapy for patients with alcohol-associated liver disease.