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Méndez-Sánchez et al. Hepatoma Res 2020;6:5 I http://dx.doi.org/10.20517/2394-5079.2019.29 Page 9 of 13

organic solute transporter alpha, and organic solute transporter beta, promoting the efflux of hepatic and
[73]
intestinal BAs to systemic circulation . However, in CLDs, a decrease in these transporters has been
observed due to an inhibition in FXR signaling by the subunit NF-κβ p65 binding directly to FXR, which
inhibits its transcriptional activity, thus maintaining liver inflammation and the probable development
[74]
of HCC . In addition, DCA can disrupt the plasma membrane, causing activation of protein kinase C,
which in turn activates p38 MAPK, increasing the activation of NF-κβ pathway and resulting in sustained
[75]
inflammation . Furthermore, the NF-κβ pathway transcribes genes encoding pro-inflammatory cytokines
such as IL-6 related to the activation of the signal transducer and activator of transcription 3 pathway,
[76]
which leads to decreased apoptosis , and IL-1β related to the activation of phosphoinositide 3 Kinase-
MDM2 pathway, which negatively regulates p53, thus increasing the survival of DNA-damaged cells and
[77]
leading to the development of HCC .

Finally, recent findings have suggested an important role of DCA and cellular senescence in the
[53]
development of HCC . Cellular senescence is a protective cell response to telomere erosion or oncogene
activation with the final objective of bringing to an end the compromised cell cycle to prevent the
[78]
development of any neoplasm . Interestingly, senescent cells develop a secretory proinflammatory profile
[79]
known as senescence-associated secretory phenotype (SASP) . An experimental model in mice found that
DCA induces SASP phenotype in HSCs, which in turns favors the secretion of proinflammatory cytokines
[53]
and tumor-promoting factors associated with HCC development . It should be noted that this was an
obesity-induced mice model; nonetheless, the results of this study could be replicated in an animal model
[53]
of high-alcohol consumption to determine if there is any important variation between models .

MICROBIOTA-REGULATORS AS A THERAPEUTIC OPTION FOR HCC
Due to the close relationship between dysbiosis and HCC, it is not difficult to imagine that certain
microbiota-regulating agents have been used in several experimental studies in both humans and animals
showing encouraging results. In this context, the drugs that have shown greater efficacy are the non-
absorbable antibiotics rifaximin [80-84] and norfloxacin [85-87] by presenting an increase in the survival of
patients with cirrhosis and HCC, in addition to preventing associated complications such as hepatic
encephalopathy, portal hypertension, and spontaneous bacterial peritonitis. Other drugs included in
this therapeutic arsenal are probiotics due to their modulating effects on the gut microbiota, by trying
[88]
to restore bacterial diversity . Unfortunately, many pharmaceutical and food companies have made
significant profits with them, which is why many so-called “healthy bacterial compounds” can be
found in both pharmacies and supermarkets, making it difficult for health authorities to regulate them.
Another important option that has not proven its efficacy in cancer but has in other GI conditions such
as Clostridium difficile infection is fecal microbiota transplantation, promising to “reset” the altered
[89]
microbiota, thus improving the anti-cancer immune response and preventing its development .
Unfortunately, all these therapeutic options are still not included in the guidelines for the management of
HCC due to the lack of standardization in different populations; thus, new clinical studies that focus on
the resolution of intestinal dysbiosis for the management of HCC are necessary to increase its therapeutic
options.

CONCLUSION
ALD is one of the most prevalent CLDs worldwide, representing a major health problem for most
countries. Although it has a low potential for malignancy compared to other CLDs, its wide prevalence
represents a major health problem for most countries. In recent years, great advances have been made
in this field. To date, we know that alcohol metabolites interfere with the mitochondrial regulation
pathways via increased expression of MSP, representing an attractive research field for understanding
ALD pathogenesis. In addition, alcohol has the capacity to disturb gut microbiota, favoring the expansion