Result or (mutualistic) cause? It's pointing to the latter!
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Fungal infections and the fungal microbiome in hepatobiliary disorders, 2022
@mauritio and others I urge you to read through the whole paper. It's a very scientifically sober and factual work which converges various interrelated aspects.
Excerpts (it appears almost necessary to quote the whole thing):
Although patients with cirrhosis already have elevated faecal levels of Candida [111], patients with HCC were found to have even higher faecal proportions of Candida and C. albicans than patients with cirrhosis, but lower proportions of the genera Kazachstania, Debaryomyces, Xeromyces, Amorphotheca, and Blastobotrys [122]. In a mouse model of HCC, gavage with C. albicans resulted in exacerbated HCC volume, which was dependent on the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 6 (NLRP6) inflammasome [123]. Moreover, development of HCC in a patient with cirrhosis increases their risk of oesophageal candidiasis (OR 10.04) [113].
Specific serum anti-C. albicans IgG and IgM titres are increased in patients with AUD vs. controls, and interestingly, the anti-C. albicans IgG titre (but not the IgM titre) decreases significantly in patients after abstinence [55]. These changes parallel elevated faecal proportions of C. albicans in patients with AUD (vs. controls), which decrease after abstinence [55]. Similarly, plasma anti-C. albicans IgG titres are increased in patients with NAFLD and advanced fibrosis (F3-F4) vs. patients with NAFLD and no/early fibrosis (F0-F2) and vs. controls, and anti-C. albicans IgG titres correlate with the faecal C. albicans/S. cerevisiae log ratio [56]. Anti-C. albicans IgG titres hence correlate with disease activity in ALD [55] and NAFLD [56], indicating more systemic exposure to C. albicans in more severe liver disease.
Candidalysin is a secreted cytolytic peptide toxin from C. albicans that directly damages epithelial membranes, triggers a danger response signalling pathway and activates epithelial immunity [129]. C. albicans strains lacking this toxin do not activate or damage epithelial cells and are avirulent in animal models of mucosal infection [129]. The extent of cell elongation 1 (ECE1) gene encoding candidalysin was more frequently present in the stool of patients with AH than AUD [98]. Further, mice gavaged with wild-type ECE1-positive C. albicans had significantly higher serum alanine aminotransferase (ALT) levels, hepatic triglycerides and inflammation than mice gavaged with ECE1-negative C. albicans in a 2-week ethanol binge model, supporting the notion that ECE1-positive C. albicans exacerbates ethanol-induced steatohepatitis in mice [98].
Secretory IgA also binds ECE1-derived candidalysin, though this binding is reduced in patients with Crohn’s, indicating fungi-related immune dysregulation [130].
Antifungal treatment improves liver disease in various mouse models, including ethanol- and western diet-induced steatohepatitis [56, 97, 131]. Further, colonisation with C. albicans [98, 123] or Malassezia restricta [99] exacerbates liver disease. Therefore, fungi and their products contribute to liver disease.
Chronic alcohol administration increases mycobial populations and the translocation of fungal beta-glucan into the systemic circulation in mice [97, 131]. Oral administration of the antifungal amphotericin B reduces faecal fungal overgrowth and beta-glucan translocation [97]. Antifungal treatment with oral amphotericin B or caspofungin prevents ethanol-induced liver disease in mice without changing plasma bacterial lipopolysaccharide levels [97, 131].
Beta-glucan induces liver inflammation via CLEC7a on Kupffer cells, as shown in experiments employing bone marrow chimeric mice [97]. CLEC7a-dependent activation of caspase-1 via NLRP3 [134, 135] leads to increased inflammatory IL-1β expression and secretion, which subsequently contributes to hepatocyte damage and ethanol-induced liver disease [97]. CLEC7a also plays a role in diet-induced steatohepatitis, since its hepatic expression is significantly increased in patients with NASH and mice on a high-fat diet, whereas Clec7a-deficient mice and mice treated with a Clec7a-antagonist are protected from diet-induced steatohepatitis and fibrosis [136].
Rats infected with C. albicans by intraperitoneal injection develop hepatic steatosis, increased serum ALT levels, inflammatory markers, and pronounced lipid peroxidation [137]. This raises the question of how C. albicans causes liver disease. One effector could be its secreted cytolytic toxin candidalysin. Candidalysin exacerbates ethanol-induced liver disease and is associated with increased mortality in mice [98]. Candidalysin does this independently of Clec7a
Candidalysin can damage primary hepatocytes in a dose-dependent manner in vitro and is associated with liver disease severity and mortality in patients with AH [98]
The PGE2-producing fungus Meyerozyma guilliermondii was increased in mice with ethanol-induced steatohepatitis [131]. Further, supplementation with Meyerozyma guilliermondii worsens ethanol-induced liver disease
Concurrent administration of an antifungal also abrogates PGE2 formation and ethanol-induced liver disease [131].
Moreover, C. albicans is a potent inducer of the Th17 response via PGE2; PGE2 is induced by the C. albicans components mannan and β-glucan that are recognised by the mannose receptor and the Clec7a/Tlr2 pathway, respectively [147, 148].
C. albicans has evolved the capacity to produce PGE2 from arachidonic acid to promote its own colonisation in the host gut [152–154]. C. albicans mutants lacking PGE2 production (genetically missing ole2, a fatty acid desaturase) are unable to colonise the murine gastrointestinal tract
Key points:
Despite a relatively small number of fungal cells in the human body, fungi are involved in the development of liver and biliary diseases.
Various rodent models of fungal microbiome (mycobiome) modulation, including increasing the fungal burden (e.g. colonisation with fungi) or decreasing the fungal burden (i.e. via antifungals), have demonstrated the impact of the mycobiome on hepatobiliary conditions.
Fungal products including toxins and metabolites can exacerbate liver and biliary diseases.
In particular, the genus Candida and the species Candida albicans play a central role in the pathogenesis and progression of essentially all hepatobiliary conditions.
Serum antibodies against fungal populations have predictive value with regard to disease severity and survival in hepatobiliary diseases.
Conclusions
Mycobiome changes have now been established in essentially all hepatobiliary conditions. However, they are still a kind of dark matter, as we often do not know their true identity and characteristics, since we cannot culture many of them. [...]
Further, they do not colonise mice easily, so we do not have good mouse models. Nevertheless, we know that some fungi are hepatotoxic themselves and not just bystanders – for example, rodents colonised with C. albicans develop liver disease without additional stimuli.
Fungi might hence possibly exacerbate liver disease in a two-hit model, one hit being alcohol, western diet, or a toxin, and another hit being the presence and deleterious impact of fungi.
We are learning more and more about the mechanisms by which fungi contribute to liver disease, be it via fungal cell wall components or secreted toxins, such as beta-glucans or candidalysin, or fungal metabolites including prostaglandins.
Wild! Profound implications for clinical practice and the foundational models of hepatobiliary diseases!
