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Chronic liver disease and its complications are a significant global health burden. Changes in fungal communities (mycobiome), an integral component of the gut microbiome, are associated with and contribute to the development of liver disease. Fungal dysbiosis can induce intestinal barrier dysfunction and allow fungal products to translocate to the liver causing progression of disease. This review explores recent progress in understanding the compositional and functional diversity of gut mycobiome signatures across different liver diseases. It delves into causative connections between gut fungi and liver diseases. We emphasize the significance of fungal translocation, with a particular focus on fungal-derived metabolites and immune cells induced by fungi, as key contributors to liver disease. Furthermore, we review the potential impact of the intrahepatic mycobiome on the progression of liver diseases.

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.

CRIg is expressed on liver macrophages and binds Gram-positive bacteria to mediate phagocytosis, but it is not clear how its phagocytic functions contribute to liver homeostasis or disease. Here the authors report that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of alcoholic liver disease.

Background & Aims: Fucosyltransferase 2 (Fut2)-mediated intestinal α1- 2-fucosylation is important for host–microbe interactions and has been associated with several diseases, but its role in obesity and hepatic steatohepatitis is not known. The aim of this study was to investigate the role of Fut2 in a Western-style diet–induced mouse model of obesity and steatohepatitis. Methods: Wild-type (WT) and Fut2-deficient littermate mice were used and features of the metabolic syndrome and steatohepatitis were assessed after 20 weeks of Western diet feeding. Results: Intestinal α1-2-fucosylation was suppressed in WT mice after Western diet feeding, and supplementation of α1-2-fucosylated glycans exacerbated obesity and steatohepatitis in these mice. Fut2-deficient mice were protected from Western diet–induced features of obesity and steatohepatitis despite an increased caloric intake. These mice have increased energy expenditure and thermogenesis, as evidenced by a higher core body temperature. Protection from obesity and steatohepatitis associated with Fut2 deficiency is transmissible to WT mice via microbiota exchange; phenotypic differences between Western diet–fed WT and Fut2-deficient mice were reduced with antibiotic treatment. Fut2 deficiency attenuated diet-induced bile acid accumulation by altered relative abundance of bacterial enzyme 7-α-hydroxysteroid dehydrogenases metabolizing bile acids and by increased fecal excretion of secondary bile acids. This also was associated with increased intestinal farnesoid X receptor/fibroblast growth factor 15 signaling, which inhibits hepatic synthesis of bile acids. Dietary supplementation of α1-2-fucosylated glycans abrogates the protective effects of Fut2 deficiency. Conclusions: α1-2-fucosylation is an important host-derived regulator of intestinal microbiota and plays an important role for the pathogenesis of obesity and steatohepatitis in mice.

BackgroundAlcohol-associated liver disease (ALD) is an important cause of morbidity and mortality worldwide. The intestinal microbiota is involved in the development and progression of ALD; however, little is known about commensal fungi therein.MethodsWe studied the dynamic changes of the intestinal fungal microbiome, or mycobiome, in 66 patients with alcohol use disorder (AUD) and after 2 weeks of alcohol abstinence using internal transcribed spacer 2 (ITS2) amplicon sequencing of fecal samples.ResultsPatients with AUD had significantly increased abundance of the genera Candida, Debaryomyces, Pichia, Kluyveromyces, and Issatchenkia, and of the species Candida albicans and Candida zeylanoides compared with control subjects. Significantly improved liver health markers caspase-cleaved and intact cytokeratin 18 (CK18-M65) levels and controlled attenuation parameter (CAP) in AUD patients after 2 weeks of alcohol abstinence were associated with significantly lower abundance of the genera Candida, Malassezia, Pichia, Kluyveromyces, Issatchenkia, and the species C. albicans and C. zeylanoides. This was mirrored by significantly higher specific anti-C. albicans immunoglobulin G (IgG) and M (IgM) serum levels in AUD patients in relation to control participants, and significantly decreased anti-C. albicans IgG levels in AUD subjects after 2 weeks of abstinence. The intestinal abundance of the genus Malassezia was significantly higher in AUD subjects with progressive liver disease compared with non-progressive liver disease.ConclusionIn conclusion, improved liver health in AUD patients after alcohol abstinence was associated with lower intestinal abundances of Candida and Malassezia, and lower serum anti-C. albicans IgG levels. Intestinal fungi might serve as a therapeutic target to improve the outcome of patients in ALD.

Alcohol-related liver disease is a public health care burden globally. Only 10–20% of patients with alcohol use disorder have progressive liver disease. This study aimed to identify lipid biomarkers for the early identification of progressive alcohol-related liver disease, which is a key step for early intervention. We performed untargeted lipidomics analysis in serum and fecal samples for a cohort of 49 subjects, including 17 non-alcoholic controls, 16 patients with non-progressive alcohol-related liver disease, and 16 patients with progressive alcohol-related liver disease. The serum and fecal lipidome profiles in the two patient groups were different from that in the controls. Nine lipid biomarkers were identified that were significantly different between patients with progressive liver disease and patients with non-progressive liver disease in both serum and fecal samples. We further built a random forest model to predict progressive alcohol-related liver disease using nine lipid biomarkers. Fecal lipids performed better (Area Under the Curve, AUC = 0.90) than serum lipids (AUC = 0.79). The lipid biomarkers identified are promising candidates for the early identification of progressive alcohol-related liver disease.