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Page 8 of 13 Méndez-Sánchez et al. Hepatoma Res 2020;6:5 I http://dx.doi.org/10.20517/2394-5079.2019.29

immunity caused by the suppression of TLR-4. In addition, chronic alcohol consumption has been
+
associated with immunosuppression though a reduced recruitment of CD8 T cells, an important group of
[52]
cells responsible for the anti-tumor response in the human body .

CHANGES IN THE GUT MICROBIOTA OF HCC PATIENTS
The gut microbiota undergoes an important change in the guests with early HCC. In obesity-induced
mouse models, a greater number of Clostridium species has been found [53,54] , while in humans an
[56]
[55]
important growth of Escherichia coli , Actinobacteria, Gemmiger, and Parabacteroides species has
been reported. In addition, due to the large number of bacteria that coexists in the body and the bacterial
translocation caused by a leaky gut, it is not uncommon to find metabolically active bacteria within richly
[57]
vascularized tumors attracted through a chemotactic gradient of the necrotic cell debris . In the case of
HCC, Helicobacter species have been found with some frequency in this type of tumor tissue [58-60] . In fact,
this relationship is so important that an influence of the gut microbiota in the effectiveness and toxicity of
certain chemotherapeutic agents has been pointed out, especially with the immune checkpoint inhibitors
through the interaction among PAMPs, antigen-presenting cells, and TLRs, which leads to an adaptive
[57]
immune response that modifies the pharmacodynamics of these types of agents . Moreover, both animal
and human studies have found a significant correlation between alcohol consumption and a disturbance in
the Lactobacillus to Bifidobacterium ratio, with an increase in pathogenic bacteria (namely, Proteobacteria
and Bacilli). Interestingly, this ratio derangement has different presentations according to alcohol
consumption habits, duration, and liver disease stage [61,62]

Looking at other examples of HCC development related to microbiota imbalances in hepatology, we
can describe the evidence regarding chronic viral hepatitis B and C. Chronic hepatitis B (CHB) patients
show lower bacterial diversity (namely, an increase of Firmicutes and a decrease of Bacterioidetes). There
is an increased concentration of H S- and CH SH- producing phylotypes (Fusobacterium, Filifactor,
3
2
Eubacterium, Parvimonas, and Treponema) that may produce small bowel bacterial overgrowth,
[63]
potentially involved in cirrhosis and HCC development . However, the impact of gut microbiota
derangements in CHB patients on hepatocytes neoplastic transformation is different from that of chronic
[64]
hepatitis C patients . In fact, obesity and/or diabetes stimulate cellular oncogenesis via gut microbiota
derangement (i.e., an abundance of Bacteroidetes and, at a genus level, Prevotella, Acinetobacter,
Veillonella, Phascolarctobacterium, and Faecalibacterium abundance) in HCC patients [65-67] .

Moreover, both interferon and new interferon-free direct antivirals successfully treated HCC patients
presenting a permanent chronic inflammatory state triggered by an altered gut microbiota with potential
HCC promotion [68-70] .

MOLECULAR INVOLVEMENT OF THE BILE ACIDS
Bile acids (BAs) are amphipathic molecules obtained from cholesterol synthesized in the liver, which play
an important role in the emulsification of fats obtained from the diet to facilitate their absorption, in
[71]
addition to important regulatory effects on the signaling pathways of glucose, lipids, and amino acids .
In a healthy host, most of the BAs’ pool is reabsorbed by active transport in the terminal ileum, while the
rest is dehydroxylated by the intestinal microbiota, such as the secondary BAs deoxycholic acid (DCA) and
[72]
lithocholic acid .

The disruption in bacterial diversity of the host induced by ALD brings with it an important change in the
BAs’ pool by upregulating bacterial dehydroxylation, resulting in an increase in DCA synthesis, known
for its important cytotoxic and carcinogenic effects. It is known that, under conditions of accumulation
of BAs, activation of farnesoid X receptor (FXR) induces the expression of the bile salt export pump,