The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease

Abstract

Background & Aims: Alcohol-associated liver disease is a leading indication for liver transplantation and a leading cause of mortality. Alterations to the gut microbiota contribute to the pathogenesis of alcohol-associated liver disease. Patients with alcohol-associated liver disease have increased proportions of Candida spp. in the fecal mycobiome, yet little is known about the effect of intestinal Candida on the disease. Herein, we evaluated the contributions of Candida albicans and its exotoxin candidalysin in alcohol-associated liver disease. Methods: C. albicans and the extent of cell elongation 1 (ECE1) were analyzed in fecal samples from controls, patients with alcohol use disorder and those with alcoholic hepatitis. Mice colonized with different and genetically manipulated C. albicans strains were subjected to the chronic-plus-binge ethanol diet model. Primary hepatocytes were isolated and incubated with candidalysin.Results: The percentages of individuals carrying ECE1 were 0%, 4.76% and 30.77% in non-alcoholic controls, patients with alcohol use disorder and patients with alcoholic hepatitis, respectively. Candidalysin exacerbates ethanol-induced liver disease and is associated with increased mortality in mice. Candidalysin enhances ethanol-induced liver disease independently of the bglucan receptor C-type lectin domain family 7 member A (CLEC7A) on bone marrow-derived cells, and candidalysin does not alter gut barrier function. Candidalysin can damage primary hepatocytes in a dose-dependent manner in vitro and is associated with liver disease severity and mortality in patients with alcoholic hepatitis. Conclusions: Candidalysin is associated with the progression of ethanol-induced liver disease in preclinical models and worse clinical outcomes in patients with alcoholic hepatitis.Lay summary: Candidalysin is a peptide toxin secreted by the commensal gut fungus Candida albicans. Candidalysin enhances alcohol-associated liver disease independently of the b-glucan receptor CLEC7A on bone marrow-derived cells in mice without affecting intestinal permeability. Candidalysin is cytotoxic to primary hepatocytes, indicating a direct role of candidalysin on ethanol-induced liver disease. Candidalysin might be an effective target for therapy in patients with alcohol-associated liver disease.Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

Therapeutic manipulation of gut microbiota by polysaccharides of Wolfiporia cocos reveals the contribution of the gut fungi-induced PGE2 to alcoholic hepatic steatosis

“…In the setting of alcoholic liver diseases, overgrowth of Candida and the decrease of fungal diversity were found in the patients with different phases of liver diseases covering non-progressive alcoholic liver diseases, alcoholic hepatitis, and alcoholic cirrhosis. 11,27 In this study, we observed an overgrowth of fungi in the gut of mice with chronic ethanol feeding and further isolated a strain of M. guilliermondii that was enriched in the feces of ethanol-fed mice. By using a fungi-free mice model, we confirmed that the enrichment of M. guilliermondii in gut aggravated the fatty accumulation and inflammatory damages in liver of the ethanol diet-fed mice.…”

Bridelia speciosa Müll.Arg. Stem bark Extracts as a Potential Biomedicine: From Tropical Western Africa to the Pharmacy Shelf

“…This inhibitory effect is consistent with its major content in total phenolic compounds [24,25], as confirmed by both colorimetric assays (Table 1) and independent HPLC-fluorimetric analysis ( Table 7). While considering both the incidence of C. albicans opportunistic infections occurring in liver disorders [50] and the traditional use of Bridelia genus [9], a pharmacological investigation was subsequently performed to explore anti-proliferative effects against the liver cancer HepG2 cell line and protective effects on isolated rat liver specimens challenged with the LPS pro-inflammatory stimulus. The HepG2 cell viability was evaluated through the MTT test, which revealed a stimulatory effect induced by methanol extract, up to 48 hours following treatment (Figure 1).…”

Gut microbiota in non‐alcoholic fatty liver disease and alcohol‐related liver disease: Current concepts and perspectives

“…It also correlates with a higher level of serum endotoxin and increased intestinal tumor necrosis factor‐α levels, as well as increased levels of nitric oxide, IL‐6, and IL‐8 . Another recent discovery is that patients with ALD not only have bacterial dysbiosis, but also show reduced fungal diversity, as well as Candida overgrowth . Indeed, using antifungal agents in mouse models has been shown to decrease β­glucan translocation and ameliorate alcohol­induced liver injury produced through the C­type lectin domain family 7 member A receptor on hepatic Kupffer cells .…”