Intestinal Fungal Dysbiosis and Systemic Immune Response to Fungi in Patients With Alcoholic Hepatitis

Abstract

Chronic alcohol consumption causes increased intestinal permeability and changes in the intestinal microbiota composition, which contribute to the development and progression of alcohol‐related liver disease. In this setting, little is known about commensal fungi in the gut. We studied the intestinal mycobiota in a cohort of patients with alcoholic hepatitis, patients with alcohol use disorder, and nonalcoholic controls using fungal‐specific internal transcribed spacer amplicon sequencing of fecal samples. We further measured serum anti–Saccharomyces cerevisiae antibodies (ASCA) as a systemic immune response to fungal products or fungi. Candida was the most abundant genus in the fecal mycobiota of the two alcohol groups, whereas genus Penicillium dominated the mycobiome of nonalcoholic controls. We observed a lower diversity in the alcohol groups compared with controls. Antibiotic or steroid treatment was not associated with a lower diversity. Patients with alcoholic hepatitis had significantly higher ASCA levels compared to patients with alcohol use disorder and to nonalcoholic controls. Within the alcoholic hepatitis cohort, patients with levels of at least 34 IU/mL had a significantly lower 90‐day survival (59%) compared with those with ASCA levels less than 34 IU/mL (80%) with an adjusted hazard ratio of 3.13 (95% CI, 1.11‐8.82; P = 0.031). Conclusion: Patients with alcohol‐associated liver disease have a lower fungal diversity with an overgrowth of Candida compared with controls. Higher serum ASCA was associated with increased mortality in patients with alcoholic hepatitis. Intestinal fungi may serve as a therapeutic target to improve survival, and ASCA may be useful to predict the outcome in patients with alcoholic hepatitis.

Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting

“…Taxonomic changes in fungi are largely characterised by a decrease in fungal diversity and overgrowth of Candida species in patients with AUD and AH. This appears to be mostly independent from the stage of liver disease 118 119. Although increased intestinal permeability is present in about 50% of patients with AUD and early stages of liver disease,117 paracellular tight junction disruption is more common in cirrhosis and AH 54…”

Gut microbiota in non‐alcoholic fatty liver disease and alcohol‐related liver disease: Current concepts and perspectives

“…It also correlates with a higher level of serum endotoxin and increased intestinal tumor necrosis factor‐α levels, as well as increased levels of nitric oxide, IL‐6, and IL‐8 . Another recent discovery is that patients with ALD not only have bacterial dysbiosis, but also show reduced fungal diversity, as well as Candida overgrowth . Indeed, using antifungal agents in mouse models has been shown to decrease β­glucan translocation and ameliorate alcohol­induced liver injury produced through the C­type lectin domain family 7 member A receptor on hepatic Kupffer cells .…”

The NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis

“…Alcohol consumption is also associated with alterations in the gut and fungal microbiome depending on the stage of liver disease. 36 A decrease of Bacteroidetes and Lactobacillus species was detected for patients with ALD, whereas Proteobacteria were increased. Additionally, dysbiosis changes the microbial metabolites such as elevated endotoxin production and reduced levels of amino acids and saturated long-chain fatty acids.…”

“…Consequently, disruption of the gut barrier facilitates the translocation of bacteria and fungi as well as their products, e.g., LPS or β-glucan, from human gut to liver. 36,62,63 Furthermore, serum analysis of healthy humans exposed to a single drink containing 0.85 g ethanol per kg body weight resulted in significant upregulation of ATP and uric acid, which are both known endogenous activators of the NLRP3 inflammasome. 41 However, to date there are only in vitro and animal studies but no human study that examines the concrete context of NLRP3 inflammasome in patients with proven ASH.…”