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Page 2 of 13 Méndez-Sánchez et al. Hepatoma Res 2020;6:5 I http://dx.doi.org/10.20517/2394-5079.2019.29

Keywords: Alcoholic liver disease, gut microbiota, dysbiosis, hepatocellular carcinoma

INTRODUCTION
The metabolic effects of alcohol in humans has been a topic of great interest for many years due to the
important relationship between excessive alcohol consumption and disease even reaching to cancer
development. In this context, The Global Burden of Disease Study 2015 reported the primary liver cancer
incidence, mortality, and disability-adjusted life-years of 195 countries from 1990 to 2015. Surprisingly,
the cases of incident liver cancer increased by 75% between 1990 and 2015. Alcohol-induced liver cancer
globally accounted for 245,000 (30%) deaths with important variations between countries and sex. Only
in 2015, alcohol caused 204,000 [95% uncertainty interval (UI), 177,000-240,000] liver cancer cases in men
and 45,000 (95% UI, 38,000-54,000) cases among women. Eastern Europe was the geographical region
which contributed with the most alcohol-induced liver cancer cases in the world, accounting for 53% of
[1]
[2]
them . According to WHO statistics, alcohol is involved in more than 200 different diseases . Among
them, gastrointestinal (GI) disorders (mainly cirrhosis) represent the third cause in mortality secondary
[3]
to excessive alcohol consumption . Interestingly, the metabolism of alcohol goes beyond the liver; in
recent years, the role of the gut-liver axis in the development and aggravation of alcoholic liver disease
[4,5]
(ALD) has emerged as an important element to consider . The gut microbiota and a selected group of
catalytic enzymes of the GI tract are key elements in ethanol metabolism and its passage to systemic
circulation. Furthermore, evidence has shown carcinogenic effects of different alcohol and gut metabolites
in ALD patients, bringing new perspectives in the development of hepatocellular carcinoma (HCC) in this
group of subjects. For this reason, this review discusses in a systematic way the role of alcohol-induced
dysbiosis in the development of ALD and its progression to HCC, starting with the different metabolic
pathways of ethanol within the human body and its deregulation in chronic alcohol consumption. Then,
the mechanisms of alcohol-induced dysbiosis with the consequent liver injury and hepatocarcinogenesis
are addressed and finally the future perspectives of microbiota-regulating drugs as adjuvants for HCC
treatment are assessed.

ALCOHOLIC LIVER DISEASE AND HCC
For the development of ALD, the fulfillment of two factors is generally necessary; one is an excessive
alcohol consumption, defined as ingestion of > 20 g/day in females and > 30 g/day in males, and the second
[3]
one is the chronicity of this consumption . On its own, ALD is one of the less frequent etiologies that
[6,7]
progress to HCC ; however, its high prevalence continues to position it as one of the most important
[8]
chronic liver diseases (CLDs) for public health . Recently, our group of work conducted a study to
determine the main etiologies of cirrhosis worldwide [Figure 1] finding interesting results among
countries .
[9]
In a healthy person, alcohol is metabolized to acetaldehyde mainly in the liver by the alcohol
dehydrogenase (ADH) and the microsomal ethanol-oxidizing system (MEOS), and to a lesser extent
it is also metabolized in the GI tract through ADH, MEOS, and the gut microbiota . Several factors
[10]
predispose the development and progression of ALD to its final stage of HCC, the most important being
genetic predisposition, age, female sex, pre-existing liver disease, and daily alcohol consumption .
[5]
Similarly, the GI tract has its own factors that predispose the metabolism and systemic absorption of
ethanol and therefore the severity of ALD. An example of this is the diminished enzymatic activity of ADH
in the stomach commonly seen in young women, elderly, alcoholics, when fasting, and after treatment with
H2-receptor antagonists. Other situations that favor systemic absorption of ethanol are delayed gastric
[10]
emptying, chronic atrophic gastritis, and gastric lesion associated with Helicobacter pylori . Nonetheless,
in ALD, there is an increase in the metabolization of ethanol to acetaldehyde by the cytosolic enzyme