Related Experiment Video
Updated: Aug 12, 2025
Assessment of Glutamine as a Fuel Source for Alveolar Macrophages Exposed to Chronic Ethanol Using an Extracellular Flux Bioanalyzer
Published on: November 15, 2024
Malassezia restricta promotes alcohol-induced liver injury
Suling Zeng1,2, Phillipp Hartmann1,3,4, Minji Park5
1Department of Medicine, University of California San Diego, La Jolla, California, USA.
Abstract:
Chronic alcohol consumption is associated with intestinal fungal dysbiosis, yet we understand little about how alterations of intestinal fungi (mycobiota) contribute to the pathogenesis of alcohol-associated liver disease. By reanalyzing internal transcribed spacer 2 amplicon sequencing of fecal samples from a cohort of 66 patients with alcohol use disorder for presence (as opposed to relative abundance) of fungal species, we observed that the presence of Malassezia restricta was associated with increased markers of liver injury. M. restricta exacerbates ethanol-induced liver injury both in acute binge and chronic ethanol-feeding models in mice. Using bone marrow chimeric mice, we found that the disease exacerbating effect by M. restricta was mediated by C-type lectin domain family 4, member N on bone marrow-derived cells. M. restricta induces inflammatory cytokines and chemokines in Kupffer cells through C-type lectin domain family 4, member N signaling. Targeting fungal pathobionts might be a therapeutic strategy for alcohol-associated liver disease.
Insights
The presence of the fungus Malassezia restricta is linked to liver injury in patients with alcohol use disorder. This fungus worsens alcohol-related liver damage by activating immune cells, suggesting it as a therapeutic target.
Area of Science:
- Microbiology
- Hepatology
- Immunology
Background:
- Chronic alcohol consumption leads to gut fungal dysbiosis.
- The role of intestinal fungi in alcohol-associated liver disease (AALD) pathogenesis is poorly understood.
Purpose of the Study:
- To investigate the association between intestinal mycobiota and liver injury in patients with alcohol use disorder.
- To determine the role of Malassezia restricta in exacerbating ethanol-induced liver injury.
Main Methods:
- Reanalysis of internal transcribed spacer 2 amplicon sequencing data from 66 patients with alcohol use disorder.
- Murine models of acute binge and chronic ethanol feeding.
- Bone marrow chimeric mice experiments to identify the cellular mechanisms.
Main Results:
- The presence of Malassezia restricta was associated with increased markers of liver injury in patients.
- M. restricta exacerbated ethanol-induced liver injury in mouse models.
- The exacerbating effect of M. restricta was mediated by C-type lectin domain family 4, member N (CLEC4N) on bone marrow-derived cells, leading to inflammatory cytokine and chemokine production in Kupffer cells.
Conclusions:
- Malassezia restricta is a key fungal pathobiont contributing to alcohol-associated liver disease progression.
- CLEC4N signaling in myeloid cells is a critical pathway for M. restricta-induced liver injury.
- Targeting fungal pathobionts like M. restricta represents a potential therapeutic strategy for AALD.
