The mechanism of dysbiosis in alcoholic liver disease leading to liver cancer

Abstract

Currently, alcoholic liver disease (ALD) is one of the most prevalent chronic liver diseases worldwide, representing one of the main etiologies of cirrhosis and hepatocellular carcinoma (HCC). Although we do not know the exact mechanisms by which only a selected group of patients with ALD progress to the final stage of HCC, the role of the gut microbiota within the progression to HCC has been intensively studied in recent years. To date, we know that alcohol-induced gut dysbiosis is an important feature of ALD with important repercussions on the severity of this disease. In essence, an increased metabolism of ethanol in the gut induced by an excessive alcohol consumption promotes gut dysfunction and bacterial overgrowth, setting a leaky gut. This causes the translocation of bacteria, endotoxins, and ethanol metabolites across the enterohepatic circulation reaching the liver, where the recognition of the pathogen-associated molecular patterns via specific Toll-like receptors of liver cells will induce the activation of the nuclear factor kappa-B pathway, which releases pro-inflammatory cytokines and chemokines. In addition, the mitogenic activity of hepatocytes will be promoted and cellular apoptosis will be inhibited, resulting in the development of HCC. In this context, it is not surprising that microbiota-regulating drugs have proven effectiveness in prolonging the overall survival of patients with HCC, making attractive the implementation of these drugs as co-adjuvant for HCC treatment.

Gut Microbiota in Metabolic-associated Fatty Liver Disease and in Other Chronic Metabolic Diseases

“…Several studies have analyzed the composition and role of the gut microbiome in different states of disease and have found correlations with metabolic pathologies, such as obesity, T2DM, atherosclerosis, MAFLD, irritable bowel syndrome, even some cutaneous problems, like atopic dermatitis, and psoriasis, among others (Table 1). 9,[50][51][52][53][54][55][56][57][58][59][60][61][62][63][64] Obesity: Most of the evidence that links changes in the…”

“…1). 63 Lean non-alcoholic fatty liver disease continues to be an outstanding and interesting topic to discuss. In a study performed by Chen et al, 64 lean healthy subjects were found to have different microbiota and BA composition compared to lean non-alcoholic fatty liver disease patients, which have increased BA levels and bacteria species involved with BA metabolism, such as those in the Clostridium genus, the Ruminococcaceae family, and the Dorea genus, and a reduction of protective bacteria, like Marvinbryantia and Christensellenaceae R7 group.…”

“…90 Drugs like norfloxacin and rifaximin, the latter being capable of inducing overgrowth of beneficial bacteria such as Bifidobacterium, Faecalibacterium, and Lactobacillus, have favored an increase in the survival of patients with cirrhosis and HCC, as well as prevented associated complications, like hepatic encephalopathy, portal hypertension, and spontaneous bacterial perito-nitis. 63 A meta-analysis conducted by Pan et al 60 compared the mechanisms of action of a wide variety of probiotics used in MAFLD treatment and found that the most predominant was the reduction of inflammatory factors (C-reactive protein and TNF-α). Other less determinant findings were the regulation of NF-κB and a reduction of serum liver enzymes (alanine aminotransferase, gamma-glutamyltranspeptidase, and aspartate aminotransferase) and fibrotic factors (TGF-β).…”

“…90 Drugs like norfloxacin and rifaximin, the latter being capable of inducing overgrowth of beneficial bacteria such as Bifidobacterium , Faecalibacterium , and Lactobacillus , have favored an increase in the survival of patients with cirrhosis and HCC, as well as prevented associated complications, like hepatic encephalopathy, portal hypertension, and spontaneous bacterial peritonitis. 63 …”

The History of Alcoholic Liver Disease: From an Unrecognized Disease to One of the Most Frequent Diseases in Hepatology

“…He also emphasized that alcohol may change the quality of gut bacteria [ 107 , 108 , 109 , 110 , 111 ]. Intestinal dysbiosis and increased intestinal permeability have a key role in the ALD pathogenesis [ 112 ]. In fact, alcohol increases the gut permeability to endotoxin/LPS.…”