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Page 8 of 13 Best et al. Hepatoma Res 2020;6:62 I http://dx.doi.org/10.20517/2394-5079.2020.56

Genetic variability is not completely explained by these common aforementioned variants and many of the
phenotypic differences potentially result from gene-environment interactions. NAFLD development and
progression are also modulated by epigenetic factors, in particular microRNAs (miRNAs). At the post-
transcriptional level, they control many complementary target mRNAs. Their dysregulation have a high
predictive value in NAFLD development and progression [73,74] . Epigenetic changes, which cause aberrant
DNA methylation, as well as the expression of various micro-RNAs (e.g., miR-21, miR-29, miR-23, miR-155,
miR-221, miR-222, miR-106, miR-93, and miR-519) are additive drivers of carcinogenesis. There is a direct
influence on the most relevant tumor-associated signal cascades [transforming growth factor beta, wingless
and INT-1 (Wnt)/b-catenin, mitogenactivated protein kinase, and phosphatidylinositol 3-kinase/AKT/
[75]
mammalian target of rapamycin] .

GUT MICROBIOME ANALYSES AS FUTURE PREDICTORS OF HCC RISK
Distinct changes or shifts in the composition of intestinal bacteria have been described for different
intestinal metabolic and inflammatory diseases [76-78] . Shifts of certain bacterial strains may also affect the
formation of different bacterial-derived metabolic active components such as short-chain fatty acids, bile
acids, ethanol, cytokines, or other inflammatory metabolites that may affect the host and possibly promote
[79]
cancer-related risk factors or diseases . The microbiota of an obese host has an impact on bodyweight
and gut permeability, and it affects the release of gut-derived components that may also influence the
progression of inflammatory mechanisms and promote the formation of cancer. Mouse models of fecal
[80]
microbiota transfer (FMT) from obese to lean animals could show that microbiota affect bodyweight .
FMT is a potential therapeutic tool that has been used to treat Clostridium difficile infections . In mouse
[81]
studies, FMT was shown to be a useful treatment to increase abundances of beneficial bacterial groups such
as Christensenellaceae and Lactobacillus to alleviate the progression of NASH-development .
[82]

The modulation of the gut microbiota by FMT to treat or study different metabolism-related diseases
[83]
has been taken into account for many years . It has been shown that antibiotic treatments, in order to
[84]
modulate the gut microbiota, may reduce the risk of hepatic carcinogenesis . In a high fat diet mouse
[85]
model of NASH, antibiotic treatments were associated with a reduction of toxic secondary bile acids .
NAFL and especially its progressive inflammatory form NASH are often related to the formation of HCC.
Here, nutrition, metabolic disturbances, and related comorbidities such as diabetes may influence the
composition of the gut microbiota. Changes in the abundances of different bacterial groups have been
described within different patient groups.

The metabolism of certain bacterial groups affects the mucosal barrier, hepatic inflammation, fibrogenesis,
[86]
and tumorigenesis . The gut microbiota has an impact on energy balance, altering the uptake of calories
[87]
derived from food and even alcohol . Emerging data indicate that certain characteristic changes in the
gut microbiome are associated with NAFLD and even with cirrhosis, which is a main driver of HCC-
development [76,88,89] . It has not only been shown in NAFLD-related HCC, but also in viral hepatitis-related
HCC (hepatitis B) that makes a modification of specific gut microbiota, a potential therapeutic option for
HCC .
[90]
In a study comparing NASH and NASH-HCC patients with or without cirrhosis, alterations in bacterial
groups regulating bile acid metabolism had an impact on hepatic fibrogenesis and liver injury. Alterations
of the bile acid pool was accompanied with increased abundances of different bacterial strains, especially
[91]
Lactobacilli and Bacteroides which were associated with changed liver stiffness and liver injury . In
NASH patients, the abundance of bile salt hydrolase (an enzyme involved in deconjugation of bile acids)
expressing bacteria is shifted, which leads to increased bile acid levels as well as an altered composition of
the bile acid pool tending to an increased amount of secondary conjugated bile acids . Changes within the
[92]