The role of Candida albicans in alcohol-related liver disease

• Applicant: Dr. David Schöler
• Subject Area: Gastroenterology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513071097

Alcohol-related liver disease (ARLD) can be transmitted via fecal microbiota. Colonization of germ-free mice with feces from patients with alcoholic hepatitis exacerbates ethanol-induced liver disease, compared with feces from conventionally colonized mice. Microbiome research has largely focused on intestinal bacteria. However, the gut microbiota also contains commensal fungi, called the intestinal mycobiome. Preclinical and translational research document the importance of the mycobiome for ARLD, but very little is known about molecular mechanisms, host-fungal immune interactions and the contribution of specific fungi to inflammation and disease progression. Preliminary human results demonstrated that the fecal mycobiome from patients with alcohol use disorder show a proportional increase of Candida spp. We predict that C. albicans overgrowth is a pathogenic factor contributing to dysfunction of the gut-liver axis in ARLD by driving Th17 cell expansion contributing to liver inflammation and damage. CD4+ T cells that produce the key cytokine IL17A are a distinct T helper cell lineage, termed Th17 cells. Th17 cells are regarded central orchestrators of immune responses against extracellular bacteria and fungi. Recent data indicate that C. albicans was the only fungus driving a dominant Th17 response in humans. The central goal of this study is to analyze the contribution of C. albicans-specific T cell response to ARLD. Aim 1) Migration of C. albicans-specific CD4+ T cells from the intestine to the liver will be studied in a mouse model of chronic ethanol feeding. Mice will be subjected to chronic plus binge ethanol feeding, CD4+ T cells will be isolated from mesenteric lymph nodes, portal vein blood, liver and systemic circulation, and stimulated with C. albicans lysates. Kaede mice will also be used to directly track migration of CD4+ T cells to the liver. For all planned experiments loss and gain of function of the intestinal mycobiome will be used.Aim 2) The contribution of C. albicans-specific CD4+ T cells to ethanol-induced liver disease in mice will be studied using two approaches in combination with C. albicans colonization and antifungal treatment in mice: i) T-cell adoptive transfer to proof that transfer of C. albicans-specific CD4+ T cells increases ethanol-induced liver disease in mice. ii) Candida-specific TCR transgenic mouse. TCR transgenic T cells recognize endogenous Candida spp. antigens allowing to functionally analyze the pathogen-specific T cell response. For T-cell adoptive transfer, an in vivo stimulation with C. albicans in mice and ex vivo restimulation for the expansion of C. albicans-specific Th17 cells will be used. In all groups of mice ethanol-induced liver disease will be evaluated. In addition, intestinal permeability, microbial translocation and dysbiosis will be assessed through analysis of epithelial tight junctions, culturing methods and ITS/16S rRNA sequencing of fecal samples.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Bernd Schnabl