The Role of the Intestinal Mycobiome in Alcoholic Liver Disease

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Principal Investigator: Bernd G. Schnabl
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $499,159
Funding agency: National Institute on Alcohol Abuse and Alcoholism

Project Summary
Alcohol associated health problems are a major medical burden in industrialized countries. Patients with
alcohol-associated liver disease show intestinal bacterial dysbiosis and increased intestinal permeability.
Although there is considerable progress in understanding the interaction between the host and intestinal
bacteria, the role of the intestinal fungal microbiome (also called mycobiome) in alcohol-associated liver
disease is not very well understood. Results from our laboratories indicate a proportional increase of
Candida albicans (C. albicans) and Malassezia restricta (M. restricta) in patients with alcohol use disorder.
Results from chronic ethanol administration in mice or chronic alcohol abuse in patients show that
C. albicans-specific T cell responses occur in the intestine. CD4+ T cells re-circulate to the liver, where they
re-activate by translocated C. albicans antigens, produce interleukin 17 (IL17) and contribute to progression
of ethanol-induced steatohepatitis. In addition, products from M. restricta translocate from the gut lumen to
the systemic circulation and liver. M. restricta induces liver inflammation via ligation with the Dectin-2
(Clec4n) receptor on Kupffer cells and augments ethanol-induced liver disease in mice. The testable central
hypothesis of this proposed collaborative and multidisciplinary research application implicates disturbances
in the gut fungal mycobiota as an important etiological factor in the modulation of adaptive and innate
immunity in the liver. Through the proposed study, we will characterize the host gut mycobiome and
immune response in a human cohort. We will mechanistically test our hypothesis in a mouse model of
ethanol-induced liver disease. Towards this goal, we will use pharmacological interventions,
supplementation of fungi and genetically modified mice. We predict that two pathogenic factors contribute to
dysfunction of the gut-liver axis in alcohol-associated liver disease: C. albicans overgrowth drives Th17 cell
expansion contributing to liver inflammation and damage (Aim 1). Binding of M. restricta to Dectin-2 induces
hepatic inflammation and exacerbates alcohol-associated liver disease (Aim 2). We believe these studies
will provide important insights into alcohol-mediated changes of the intestinal mycobiome that result in an
immune response contributing to alcohol-associated liver disease. Eventually this approach might lead to
new therapeutic targets for patients with alcohol-associated liver disease.

Terms: <Absolute ethanol><Adoptive Transfer><Affect><Alcohol Chemical Class><Alcohol abuse><Alcoholic Liver Diseases><Alcoholism><Alcohols><Antigens><Bacteria><Belgium><Binding><C albicans><C. albicans><C.albicans><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><California><Candida><Candida albicans><Causality><Cell Body><Cells><Chronic><Circulation><Closure by Ligation><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Data><Developed Countries><Disease><Disorder><Dysfunction><ETOH><EtOH abuse><Ethanol><Ethyl Alcohol><Etiology><Experimental Animal Model><Functional disorder><GI microbiome><Gene Modified><Gene Transcription><Generalized Growth><Genetic Transcription><Germany><Glucans><Glucose Polymer><Goals><Grain Alcohol><Growth><Gut Epithelial Permeability><Gut Hyperpermeability><Gut permeability><Health><Hepatic><Hepatic Disorder><Human><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><Immune response><Immunity><Immunological response><Industrialized Countries><Industrialized Nations><Infrastructure><Injury to Liver><Innate Immunity><Interdisciplinary Research><Interdisciplinary Study><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin-17><Intervention><Intervention Strategies><Intestinal><Intestinal Epithelial Permeability><Intestinal Hyperpermeability><Intestinal permeability><Intestines><Investigators><Kupffer Cells><Laboratories><Ligation><Liver><Liver diseases><MHC Receptor><Macrophage><Major Histocompatibility Complex Receptor><Malassezia><Mediating><Medical><Methods><Methylcarbinol><Mice><Mice Mammals><Microbiomics><Modern Man><Molecular><Molecular Interaction><Monilia><Morbidity><Morbidity - disease rate><Multidisciplinary Collaboration><Multidisciplinary Research><Murine><Mus><Mφ><Native Immunity><Natural Immunity><Nature><Non-Specific Immunity><Nonspecific Immunity><Pathogenicity Factors><Patients><Persons><Physiopathology><Pityrosporum><Polyglucoses><Population><Portal Vein><Portal vein structure><Preventative intervention><Principal Investigator><Publications><RNA Expression><Receptor Protein><Research><Research Personnel><Researchers><Ribosomal DNA><Role><Scientific Publication><Steatohepatitis><Stellate Sinusoidal Macrophage><Supplementation><T cell response><T-Cell Antigen Receptors><T-Cell Receptor><T4 Cells><T4 Lymphocytes><Testing><Therapeutic Fungicides><Therapeutic Intervention><Tissue Growth><Transcription><Transgenic Mice><United States><Universities><University Hospitals><Virulence Factors><Virus><adaptive immunity><alcohol co-abuse><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol problem><alcohol related liver disease><alcohol response><alcohol use disorder><alcohol-associated liver disease><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcohol-related liver disease><alcoholic liver injury><anti-fungal><anti-fungal agents><anti-fungal drug><bacterial microbiome><bacteriome><bowel><causation><cohort><dectin-2><design><designing><developed country><developed nation><developed nations><digestive tract microbiome><disease causation><dysbacteriosis><dysbiosis><dysbiotic><enteric microbiome><ethanol abuse><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol liver disease><ethanol response><ethanol use disorder><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><feeding><fungal microbiome><fungal microbiota><fungus><gastrointestinal microbiome><gene modification><genetically modified><gut microbiome><gut-associated microbiome><gut-liver axis><hazardous alcohol use><hepatic body system><hepatic damage><hepatic disease><hepatic inflammation><hepatic injury><hepatic organ system><hepatopathy><host response><immune system response><immunogen><immunoresponse><inflamed liver><innovate><innovation><innovative><insight><intervention for prevention><intervention therapy><interventional strategy><intestinal biome><intestinal microbiome><liver damage><liver disorder><liver inflammation><liver injury><liver macrophage><microbial><microbial consortia><microbial flora><microbial imbalance><microbiome research><microbiome science><microbiome sequencing><microbiome studies><microbiota><microflora><migration><mortality><mouse dectin-2><mouse model><multispecies consortia><murine model><mycobiome><mycobiota><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><ontogeny><pathophysiology><pharmacologic><prevent><preventing><prevention intervention><preventional intervention strategy><preventive intervention><problem alcohol use><problem drinking><problematic alcohol consumption><problematic alcohol use><rDNA><receptor><response to alcohol><response to ethanol><social role>