Candida albicans-specific Th17 cell-mediated response contributes to alcohol-associated liver disease

Alcohol-associated liver disease is accompanied by intestinal mycobiome dysbiosis, yet the impacts on liver disease are unclear. We demonstrate that Candida albicans-specific T helper 17 (Th17) cells are increased in circulation and present in the liver of patients with alcohol-associated liver disease. Chronic ethanol admin-istration in mice causes migration of Candida albicans (C. albicans)-reactive Th17 cells from the intestine to the liver. The antifungal agent nystatin decreased C. albicans-specific Th17 cells in the liver and reduced ethanol-induced liver disease in mice. Transgenic mice expressing T cell receptors (TCRs) reactive to Candida antigens developed more severe ethanol-induced liver disease than transgene-negative littermates. Adoptively transferring Candida-specific TCR transgenic T cells or polyclonal C. albicans-primed T cells exacerbated ethanol-induced liver disease in wild-type mice. Interleukin-17 (IL-17) receptor A signaling in Kupffer cells was required for the effects of polyclonal C. albicans-primed T cells. Our findings indicate that ethanol increases C. albicans-specific Th17 cells, which contribute to alcohol-associated liver disease.

Automated summary

Alcohol-associated liver disease is accompanied by dysbiosis of the intestinal mycobiome, with increased Candida albicans-specific T helper 17 (Th17) cells found in the circulation and liver of patients. Chronic ethanol administration in mice causes migration of Candida albicans-reactive Th17 cells from the intestine to the liver. The antifungal agent nystatin reduces C. albicans-specific Th17 cells in the liver and improves ethanol-induced liver disease in mice. Transgenic mice expressing T cell receptors (TCRs) reactive to Candida antigens show more severe ethanol-induced liver disease, and adoptively transferring Candida-specific TCR transgenic T cells exacerbates ethanol-induced liver disease in wild-type mice, indicating the contribution of C. albicans-specific Th17 cells to alcohol-associated liver disease.