The fundamental role of rifaximin in the treatment of hepatic encephalopathy has been recently demonstrated, but it seems to have a role in treatment of ALD too[80]

The fundamental role of rifaximin in the treatment of hepatic encephalopathy has been recently demonstrated, but it seems to have a role in treatment of ALD too[80]. The main advantage of rifaximin is that it is not absorbed and therefore presents few side effects. cells, recognize endotoxins. Several studies have exhibited the importance of gut-liver axis and new treatments have been studied in recent years to reduce progression of ALD modifying gut microbiota. It has focused attention on antibiotics, prebiotics, probiotics and synbiotics. Keywords:Alcoholic liver disease, Bacterial translocation, Dysbiosis, Prebiotics, Probiotics, Synbiotic, Gut microbiota, Endotoxin Core tip:A close anatomical and functional relationship between gut and liver exists. Blood circulated in the portal vein transfers various toxic compounds for filtration by liver. Endotoxin is usually a lipopolysaccharide derived from the cell wall of Gram unfavorable bacteria presents in the intestine, which is usually assimilated from intestinal epithelium and transported to the liver and Kupffer cells through the portal vein. A qualitative (dysbiosis) and quantitative (bacterial overgrowth) alteration of intestinal microbiome are the causes of an increase of endotoxins and subsequently, liver damage. The new treatments try to contrast dysbiosis and bacterial overgrowth decreasing evolution of alcohol liver disease. == INTRODUCTION == Alcoholic liver disease (ALD) is the cause of a high rate of morbidity and mortality worldwide. It is the commonest cause of cirrhosis in many Western countries[1]. It accounted for 3.8% of all deaths in 2004[2]. ALD consists Proscillaridin A of several types of disease such as fatty liver (steatosis), steatohepatitis, fibrosis, cirrhosis and ultimately hepatocarcinoma (HCC). Steatosis is usually reversible with alcohol abstention, but it is considered a risk factor for progression to fibrosis Proscillaridin A and cirrhosis[3,4]. The metabolism of alcohol is also regulated by intestinal bacteria (bacteriocolonic metabolism of ethanol). In 1984 Bode et al[5] exhibited a qualitative and quantitative significant difference between flora in people with alcoholism and gut microflora of a control group. Intestinal homeostasis is usually influenced by several factors such as gut motility, gastric acidity, immunological defence factors, bile salts, and colonic pH[6]. The liver strategic position confers it with the important role of translating physiological and pathological processes within the gastrointestinal tract into metabolic and immunologic outcomes[7]. == PATHOGENESIS OF ALCOHOLIC LIVER DISEASE == Alcoholic steatohepatitis (ASH) and severe ALD occur in approximately 30% of heavy drinkers[8]. The pathogenesis of ALD is usually a dynamic and unknown process characterized by several interactions that involve the immune system and metabolic intermediates of alcohol. The poor understanding of these interactions contrasted with the progress in developing specific treatments for ALD[9-11]. Ethanol metabolism-associated oxidative stress, abnormal methionine metabolism, ethanol-mediated induction of leakage of gut endotoxins, Mouse monoclonal to DDR2 and activation of Kupffer cells are all involved in the pathogenesis of ALD[12-14]. The fermentation of carbohydrates made by bacterial intestinal flora Proscillaridin A is usually itself responsible for production of endogenous ethanol. This is strongly enhanced in the presence of gut dysmotility (e.g., from obesity, diabetes, or chronic alcohol use) or an excess of carbohydrates in the diet[15]. The intestinal oxidation of alcohol results in increasing concentrations of acetaldehyde[16,17], the first and most harmful product of ethanol metabolism responsible for alteration of intestinal permeability (gut leakiness) and microbiota homeostasis. Apart from the liver, several organs contribute to ethanol metabolism resulting in acetaldehyde production, such as the pancreas, gastrointestinal tract, heart and brain[18-20]. Acetaldehyde is usually produced by bacterial alcohol dehydrogenase[21] and metabolised by aldehyde dehydrogenase in the colon[22]. In a recent study Kwon et al[23] evaluated the role of aldehyde dehydrogenase 2 deficiency in mouse in the progression of alcohol liver disease. They showed the role of acetaldehyde in hepatic inflammation and fibrosis. Acetaldehyde is usually itself responsible for mitochondrial dysfunction and altered acetaldehyde metabolism that leads to its accumulation. It determines direct hepatocyte damage forming adducts with proteins and DNA by the interactions with amino, hydroxyl, and sulfhydryl groups[24]. Acetaldehyde is also responsible for increased paracellular intestinal permeability because of a redistribution of tight junction proteins (occluding and ZO-1) and adherent junction (E-cadherin and -catenin) proteins inhibiting their phosphorylation by protein tyrosine phosphatase[25-27] (Physique1). == Physique 1. == Metabolism of alcohol. The leakiness of gut activates the transcription of nuclear factor kappaB (NF-B) gene and over-expression of nitric Proscillaridin A oxide (NO) synthesis. NO is usually synthesized fromL-arginine by nitric oxide synthases (NOS). Three isoforms of nitric oxide synthases exist: neuronal NOS (nNOS), endothelial NOS (eNOS), defined as constitutive NOS (cNOS), and inducible NOS (iNOS)[28]. NO.