{"doi":"10.1016/j.jhepr.2025.101718","title":"Peptide YY reduces cytotoxicity of Candida albicans in alcohol-associated liver disease","abstract":"BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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. IMPACT AND IMPLICATIONS: 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.","journal":"JHEP Reports","year":2025,"id":586850,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":495682,"name":"Marcos F. Fondevila","orcid":"0000-0002-5099-3421","position":1,"is_corresponding":false},{"id":1372075,"name":"Aenne Harberts","orcid":"0000-0002-0143-8106","position":2,"is_corresponding":false},{"id":1204521,"name":"Fernanda Raya Tonetti","orcid":"0000-0002-8890-4252","position":3,"is_corresponding":false},{"id":1086558,"name":"David Schöler","orcid":"0000-0002-2736-9778","position":4,"is_corresponding":false},{"id":1362636,"name":"Eliane Münte","orcid":null,"position":5,"is_corresponding":false},{"id":625161,"name":"Phillipp Hartmann","orcid":"0000-0003-3658-3335","position":6,"is_corresponding":false},{"id":647745,"name":"Cristina Llorente","orcid":"0000-0001-8135-9186","position":7,"is_corresponding":false},{"id":91993,"name":"Bernhard Hube","orcid":"0000-0002-6028-0425","position":8,"is_corresponding":false},{"id":1501940,"name":"Salomé LeibundGut-Landmann","orcid":null,"position":9,"is_corresponding":false},{"id":245705,"name":"Peter Stärkel","orcid":"0000-0003-2938-4442","position":10,"is_corresponding":false},{"id":239670,"name":"Bernd Schnabl","orcid":"0000-0002-6281-825X","position":11,"is_corresponding":false},{"id":1230995,"name":"Henriette Kreimeyer","orcid":null,"position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:59:32.191237Z","pmid":"41996830","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}