LAUSR

The importance of the “gut-liver axis” has been long established in alcoholic liver disease (ALD). The direct effects of alcohol, its metabolites, and reactive oxygen species produced during alcohol metabolism result in cellular stress in hepatocytes, release of damageassociated molecules (DAMPs), and increased hepatocyte vulnerability to inflammation-related cellular injury. Excessive alcohol use also results in gut “leakiness,” resulting in increased delivery of pathogen-derived molecular patterns (PAMPs) to the liver through the portal system. All of these gut-derived PAMPs and hepatocyte-derived DAMPs contribute to Kupffer cell (KC) and innate immune cell activation in the liver in ALD. Alcohol use was shown to change the composition of the gut microbiome by modifying the quantity, quality, and diversity of bacteria in the intestines both in humans and mice. The composition of the gut microbiome is only partially understood and it includes bacteria, fungi, and viruses. Every individual’s gastrointestinal tract contains thousands of different species of microbes, of which 99.9% belong to only a few species. The less abundant component of the microbiome is called a rare biosphere, which is more diverse and appears to have a major impact on health and disease. The fungal microbiota, also referred to as the mycobiome, is part of the rare biosphere and is a new and rapidly emerging field; scientific knowledge lags behind that of the bacterial microbiome. Increasing evidence suggests that the fungal mycobiome plays a role as a cofactor in inflammatory and metabolic disorders and in modulating the bacterial microbiome and host defense. The fungal mycobiome has been studied at mucosal sites such as the oral cavity, gastrointestinal and urogenital tracts, and the skin. Studies in healthy individuals revealed 66 different fungal genera in the fecal material where the most common genera were Saccharomyces, Candida, and Cladosporium. Recent studies have indicated a correlation between changes in the gut mycobiome and different disease conditions. glucan into the systemic circulation in mice. Administration of antifungal agents that reduced intestinal fungal overgrowth decreased b-1,3-glucan translocation and ameliorated alcoholic liver disease (ALD). In the report by Yang et al., fecal samples from patients with alcohol dependence, alcoholic hepatitis, or alcoholic cirrhosis revealed reduction in fungal species richness and diversity compared with normal controls. Decrease in intestinal fungal diversity has been found in inflammatory bowel disease. A prominent feature of the alcohol-induced fungal dysbiosis was the relative overgrowth of Candida albicans that interestingly was also described as abundant in Crohn’s disease. Candida colonization has also been shown to enhance inflammation in the airway. In Yang et al.’s study, antiSaccharomyces cerevisiae IgG antibody (ASCA) levels were significantly higher in patients with alcoholic cirrhosis compared with cirrhosis due to chronic hepatitis B infection, and ASCA serum levels correlated with mortality in patients with alcoholic cirrhosis. These observations suggest that increased and sustained exposure of the immune system to fungi such as Saccharomyces cerevisiae may contribute to alcohol-related liver cirrhosis, immune dysfunction, or both. The contention that gut-derived fungal PAMPs contribute to ALD is supported by the observation made by Yang et al., who found that in bone marrow chimera mice, b 21,3-glucan induced liver inflammation through the C-type lectin receptor, CLEC7A (Dectin-1), on KCs and possibly other bone marrow–derived immune cells as indicated by increased interleukin (IL)-1ß production. However, in addition to b-1,3-glucan, many other fungal PAMPs can activate immune cells through various pattern recognition receptors such as toll-like receptors (TLR2, 3, 4, 5, 6, and 9), Nod-like receptors (NOD1, NOD2, and NLRP3), C-type lectin receptors, and other receptors including CD14,