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• W2034801500 abstract "Alcoholic liver disease (ALD) has been among the leading causes of cirrhosis and liver-related death worldwide for decades. Early discoveries in alcoholic liver disease identified increased levels of bacterial endotoxin in the portal circulation, suggesting a role for gut-derived toxins in ALD. Indeed, alcohol consumption can disrupt the intestinal epithelial barrier and result in increased gut permeability that increasingly is recognized as a major factor in ALD. Bacterial endotoxin, lipopolysaccharide, is a prototypic microbe-derived inflammatory signal that contributes to inflammation in ALD through activation of the Toll-like receptor 4. Recent studies also have shown that alcohol consumption is associated with alterations in the gut microbiome, and the dysbalance of pathogenic and commensal organisms in the intestinal microbiome may contribute to the abnormal gut–liver axis in ALD. Indeed, bacterial decontamination improves ALD both in human and animal models. This short review summarizes recent findings and highlights emerging trends in the gut–liver axis relevant to ALD. Alcoholic liver disease (ALD) has been among the leading causes of cirrhosis and liver-related death worldwide for decades. Early discoveries in alcoholic liver disease identified increased levels of bacterial endotoxin in the portal circulation, suggesting a role for gut-derived toxins in ALD. Indeed, alcohol consumption can disrupt the intestinal epithelial barrier and result in increased gut permeability that increasingly is recognized as a major factor in ALD. Bacterial endotoxin, lipopolysaccharide, is a prototypic microbe-derived inflammatory signal that contributes to inflammation in ALD through activation of the Toll-like receptor 4. Recent studies also have shown that alcohol consumption is associated with alterations in the gut microbiome, and the dysbalance of pathogenic and commensal organisms in the intestinal microbiome may contribute to the abnormal gut–liver axis in ALD. Indeed, bacterial decontamination improves ALD both in human and animal models. This short review summarizes recent findings and highlights emerging trends in the gut–liver axis relevant to ALD. Podcast interview: www.gastro.org/gastropodcast. Also available on iTunes. The anatomy of the liver provides its close interaction with the gut where nutrients and the microbiome contribute to the maintenance of a healthy metabolism and liver. Gut-derived nutrients and other signals are delivered to the liver via the portal circulation, which has several unique features. The slow blood flow in the liver sinusoids permits interactions between gut-derived substances and hepatocytes, other liver parenchymal cells, and liver immune cells; this is promoted further by the fenestrated endothelium in the sinusoids.1Racanelli V. Rehermann B. The liver as an immunological organ.Hepatology. 2006; 43: S54-S62Crossref PubMed Scopus (876) Google Scholar The liver, as the largest immune organ, hosts the entire spectrum of immune cell repertoire and has a remarkable capacity to recruit and activate immune cells in response to gut-derived metabolic or pathogen-derived signals. The effects of gut microbiota in liver diseases has been of major interest in recent years.2Goel A. Gupta M. Aggarwal R. Gut microbiota and liver disease.J Gastroenterol Hepatol. 2014; 29: 1139-1148Crossref PubMed Scopus (75) Google Scholar A recent study placed the liver in the center of the intersections between the host and the gut commensal microbiota.3Balmer M.L. Slack E. de Gottardi A. et al.The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota.Sci Transl Med. 2014; 6: 237ra66Crossref PubMed Scopus (283) Google Scholar Interestingly, bile acid produced by the liver also can modulate the microbiome because some bacteria utilize bile acids.4Ridlon J.M. Kang D.J. Hylemon P.B. et al.Bile acids and the gut microbiome.Curr Opin Gastroenterol. 2014; 30: 332-338Crossref PubMed Scopus (706) Google Scholar The interaction between the microbiome and the host liver is of particular interest in alcoholic liver disease, in which alcohol was shown to both change the composition of the microbiome and impair intestinal integrity and barrier function.5Schnabl B. Brenner D.A. Interactions between the intestinal microbiome and liver diseases.Gastroenterology. 2014; 146: 1513-1524Abstract Full Text Full Text PDF PubMed Scopus (607) Google Scholar, 6Szabo G. Bala S. Alcoholic liver disease and the gut-liver axis.World J Gastroenterol. 2010; 16: 1321-1329Crossref PubMed Scopus (275) Google Scholar Excessive alcohol use over a prolonged period of time often results in alcoholic liver disease (ALD). The spectrum of alcoholic liver disease includes steatosis, steatohepatitis, acute alcoholic steatohepatitis, alcoholic fibrosis, and cirrhosis (Laennec’s cirrhosis). Steatosis and early steatohepatitis are reversible after cessation of alcohol use. Based on current understanding, multiple pathogenic factors are involved in the development of alcoholic liver disease. Alcohol and its metabolites induce reactive oxygen species and hepatocyte injury, through mitochondrial damage and endoplasmic reticulum stress.7Lieber C.S. Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis.Alcohol. 2004; 34: 9-19Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar, 8Cederbaum A.I. Lu Y. Wu D. Role of oxidative stress in alcohol-induced liver injury.Arch Toxicol. 2009; 83: 519-548Crossref PubMed Scopus (461) Google Scholar, 9Leung T.M. Nieto N. CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease.J Hepatol. 2013; 58: 395-398Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 10Dolganiuc A. Thomes P.G. Ding W.X. et al.Autophagy in alcohol-induced liver diseases.Alcohol Clin Exp Res. 2012; 36: 1301-1308Crossref PubMed Scopus (80) Google Scholar, 11Nassir F. Ibdah J.A. Role of mitochondria in alcoholic liver disease.World J Gastroenterol. 2014; 20: 2136-2142Crossref PubMed Scopus (74) Google Scholar, 12Fernandez-Checa J.C. Kaplowitz N. Garcia-Ruiz C. et al.Mitochondrial glutathione: importance and transport.Semin Liver Dis. 1998; 18: 389-401Crossref PubMed Scopus (190) Google Scholar There is early activation of chemokines, particularly monocyte chemoattractant protein-1, which contributes to recruitment of macrophages, and interleukin (IL)8, which recruits neutrophil leukocytes in the liver.13Mandrekar P. Ambade A. Lim A. et al.An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice.Hepatology. 2011; 54: 2185-2197Crossref PubMed Scopus (196) Google Scholar, 14Szabo G. Petrasek J. Bala S. Innate immunity and alcoholic liver disease.Dig Dis. 2012; 30: 55-60Crossref PubMed Scopus (85) Google Scholar Activation of Kupffer cells (KCs) has been identified as a central element in the pathogenesis of ALD.15Wheeler M.D. Kono H. Yin M. et al.The role of Kupffer cell oxidant production in early ethanol-induced liver disease.Free Radic Biol Med. 2001; 31: 1544-1549Crossref PubMed Scopus (216) Google Scholar, 16Enomoto N. Ikejima K. Bradford B.U. et al.Role of Kupffer cells and gut-derived endotoxins in alcoholic liver injury.J Gastroenterol Hepatol. 2000; 15: D20-D25Crossref PubMed Google Scholar Previous studies have shown that KCs and recruited macrophages in the liver are activated by bacterial endotoxin (lipopolysaccharide [LPS]) through Toll-like receptor 4 (TLR4), and that the level of LPS is increased in the portal as well as in the systemic circulation after excessive alcohol intake.17Uesugi T. Froh M. Arteel G.E. et al.Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice.Hepatology. 2001; 34: 101-108Crossref PubMed Scopus (411) Google Scholar, 18Petrasek J. Mandrekar P. Szabo G. Toll-like receptors in the pathogenesis of alcoholic liver disease.Gastroenterol Res Pract. 2010; 2010 (Epub August 17, 2010)https://doi.org/10.1155/2010/710381Crossref PubMed Scopus (75) Google Scholar These observations suggest that gut-derived LPS is a central mediator of inflammation in alcoholic steatohepatitis. Fibrosis is a dynamic and progressive process governed by stellate cell activation from inflammatory cytokines and gut-derived products.19De Minicis S. Rychlicki C. Agostinelli L. et al.Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice.Hepatology. 2014; 59: 1738-1749Crossref PubMed Scopus (197) Google Scholar Indeed, microbial components in the portal blood contribute to the progression of fibrosis and the development of portal hypertension.19De Minicis S. Rychlicki C. Agostinelli L. et al.Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice.Hepatology. 2014; 59: 1738-1749Crossref PubMed Scopus (197) Google Scholar, 20Seki E. De Minicis S. Osterreicher C.H. et al.TLR4 enhances TGF-beta signaling and hepatic fibrosis.Nat Med. 2007; 13: 1324-1332Crossref PubMed Scopus (1458) Google Scholar Advanced ALD predisposes to hepatocellular cancer: LPS-TLR4 interactions and stem cell Nanog expression seem to have mechanistic roles in animal models.21Dapito D.H. Mencin A. Gwak G.Y. et al.Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4.Cancer Cell. 2012; 21: 504-516Abstract Full Text Full Text PDF PubMed Scopus (821) Google Scholar, 22Machida K. Tsukamoto H. Mkrtchyan H. et al.Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog.Proc Natl Acad Sci U S A. 2009; 106: 1548-1553Crossref PubMed Scopus (181) Google Scholar The integrity of the intestinal mucosa is determined by the function of several components: protective layer of defensins on the intraluminal surface of the intestinal epithelium, tight junction proteins between intestinal epithelial cells, and the gut immune cells in the intestinal wall (Figure 1).5Schnabl B. Brenner D.A. Interactions between the intestinal microbiome and liver diseases.Gastroenterology. 2014; 146: 1513-1524Abstract Full Text Full Text PDF PubMed Scopus (607) Google Scholar Alcohol has both direct effects on these functions in the intestine and indirect effects by alcohol and/or its metabolites distributed via the blood stream (Figure 2).23Rao R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease.Hepatology. 2009; 50: 638-644Crossref PubMed Scopus (331) Google Scholar An acute alcohol binge causes cellular damage and death of the intestinal epithelial cells when consumed at high concentrations.24Lippai D. Bala S. Catalano D. et al.MicroRNA-155 deficiency prevents alcohol-induced serum endotoxin increase and small bowel inflammation in mice.Alcohol Clin Exp Res. 2014; 38: 2217-2224Crossref PubMed Scopus (76) Google Scholar In addition, an increase in blood alcohol levels is associated with a reduced expression of messenger RNA levels of important proteins involved in tight junctions between colon epithelial cells.25Keshavarzian A. Holmes E.W. Patel M. et al.Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage.Am J Gastroenterol. 1999; 94: 200-207Crossref PubMed Scopus (291) Google Scholar In Caco-2 intestinal epithelial cells, alcohol decreases the expression of the tight junction proteins occludin and zonula occludens-1.25Keshavarzian A. Holmes E.W. Patel M. et al.Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage.Am J Gastroenterol. 1999; 94: 200-207Crossref PubMed Scopus (291) Google Scholar, 26Wang Y. Tong J. Chang B. et al.Effects of alcohol on intestinal epithelial barrier permeability and expression of tight junction associated proteins.Mol Med Rep. 2014; 9: 2352-2356PubMed Google Scholar It has been shown that microRNA-221 is involved in the down-regulation of the tight junctions proteins in the mouse model of alcohol-induced gut permeability.25Keshavarzian A. Holmes E.W. Patel M. et al.Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage.Am J Gastroenterol. 1999; 94: 200-207Crossref PubMed Scopus (291) Google Scholar Acetaldehyde, a highly toxic metabolite of alcohol, disrupts tight junctions, thereby contributing to the increased gut permeability caused by chronic alcohol use.27Dunagan M. Chaudhry K. Samak G. et al.Acetaldehyde disrupts tight junctions in Caco-2 cell monolayers by a protein phosphatase 2A-dependent mechanism.Am J Physiol Gastrointest Liver Physiol. 2012; 303: G1356-G1364Crossref PubMed Scopus (63) Google Scholar In Caco-2 cells, alcohol also increased the expression of the circadian clock proteins, circadian locomotor output cycles kaput (CLOCK) and period circadian clock 2 (PER2), via reactive oxygen species–induced up-regulation of cytochrome P450 2E1 (CyP2E1), leading to intestinal hyperpermeability.28Forsyth C.B. Voigt R.M. Shaikh M. et al.Role for intestinal CYP2E1 in alcohol-induced circadian gene-mediated intestinal hyperpermeability.Am J Physiol Gastrointest Liver Physiol. 2013; 305: G185-G195Crossref PubMed Scopus (50) Google Scholar Further studies have shown that disruption of the circadian clock in mice resulted not only in increased intestinal permeability but also promoted alcohol-induced liver damage and inflammation.29Summa K.C. Voigt R.M. Forsyth C.B. et al.Disruption of the circadian clock in mice increases intestinal permeability and promotes alcohol-induced hepatic pathology and inflammation.PLoS One. 2013; 8: e67102Crossref PubMed Scopus (168) Google Scholar Chronic exposure of Caco-2 cells to alcohol also increased the susceptibility of these epithelial cells to infections by bacterial pathogens.30Wood S. Pithadia R. Rehman T. et al.Chronic alcohol exposure renders epithelial cells vulnerable to bacterial infection.PLoS One. 2013; 8: e54646Crossref PubMed Scopus (35) Google Scholar In vivo, deficiency in intestinal mucin-2 ameliorated ALD in mice and this was linked to increased killing of commensal bacteria and prevention of bacterial overgrowth.31Hartmann P. Chen P. Wang H.J. et al.Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice.Hepatology. 2013; 58: 108-119Crossref PubMed Scopus (159) Google ScholarFigure 2Gut liver axis in alcoholic liver disease. Alcohol consumption, both acute binge and chronic alcohol, directly affects the gut intestinal barrier at multiple levels including tight junctions between gut epithelial cells, production of mucin, recruitment and activation of inflammatory cells to the intestinal wall. In addition, the composition of the gut microbiome changes as a result of alcohol consumption. These result in increased translocation of microbial product from the gut to the liver through the portal circulation. In addition to increased levels of LPS, other microbial components may also reach the liver where in the liver sinusoids Kupffer cells and other recruited immune cells become activated and produce large amounts of pro-inflammatory cytokines, TNFa, IL-1β and IL06. Most of these cytokines further increase gut permeability, thus fueling a vicious cycle of inflammation in alcoholic hepatitis.View Large Image Figure ViewerDownload Hi-res image Download (PPT) We recently found that acute alcohol binge drinking in healthy human volunteers resulted in a significant increase in serum endotoxin levels and that this correlated with increased bacterial 16S ribosomal DNA, suggesting gut microbial origin.32Bala S. Marcos M. Gattu A. et al.Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals.PLoS One. 2014; 9: e96864Crossref PubMed Scopus (215) Google Scholar This is similar to the increased levels of serum endotoxin reported in patients with chronic alcohol consumption and liver disease.16Enomoto N. Ikejima K. Bradford B.U. et al.Role of Kupffer cells and gut-derived endotoxins in alcoholic liver injury.J Gastroenterol Hepatol. 2000; 15: D20-D25Crossref PubMed Google Scholar, 33Bode C. Kugler V. Bode J.C. Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess.J Hepatol. 1987; 4: 8-14Abstract Full Text PDF PubMed Scopus (459) Google Scholar In the animal model, we found that both acute alcohol binges and chronic alcohol administration increased serum endotoxin levels in mice.24Lippai D. Bala S. Catalano D. et al.MicroRNA-155 deficiency prevents alcohol-induced serum endotoxin increase and small bowel inflammation in mice.Alcohol Clin Exp Res. 2014; 38: 2217-2224Crossref PubMed Scopus (76) Google Scholar The acute alcohol binge resulted in minimal inflammation in the proximal intestine whereas tumor necrosis factor (TNF)α and nuclear factor-κB activation were robust after chronic alcohol feeding. The alcohol-induced intestinal inflammation correlated with reduced messenger RNA and protein levels of Reg3b and increased expression of microRNA-155 (miR-155) in the small intestine, and further studies showed that miR-155–deficient mice were protected from chronic alcohol-induced inflammation in the small intestine. Furthermore, there was no increase in serum endotoxin levels after chronic alcohol feeding in the miR-155–deficient mice, suggesting that microRNA-155 may have a role in alcohol-induced disruption of the gut integrity.24Lippai D. Bala S. Catalano D. et al.MicroRNA-155 deficiency prevents alcohol-induced serum endotoxin increase and small bowel inflammation in mice.Alcohol Clin Exp Res. 2014; 38: 2217-2224Crossref PubMed Scopus (76) Google Scholar Another recently identified regulator of gut permeability is FoxO4, which is induced by alcohol.34Chang B. Sang L. Wang Y. et al.The role of FoxO4 in the relationship between alcohol-induced intestinal barrier dysfunction and liver injury.Int J Mol Med. 2013; 31: 569-576PubMed Google Scholar It was found that alcohol significantly increased FoxO4 levels, which can regulate intestinal permeability.34Chang B. Sang L. Wang Y. et al.The role of FoxO4 in the relationship between alcohol-induced intestinal barrier dysfunction and liver injury.Int J Mol Med. 2013; 31: 569-576PubMed Google Scholar These recent studies imply the complexity of gut barrier function and highlight the multiple checkpoints at which alcohol could interfere with normal function. Perhaps the majority of the new information on the gut–liver axis in recent years is related to understanding the role of the microbiome in human health and disease. The intestinal microbiota has a major role in shaping the host immune response and commensal bacteria shape the integrity of the gut mucosa.35Kamada N. Nunez G. Regulation of the immune system by the resident intestinal bacteria.Gastroenterology. 2014; 146: 1477-1488Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar A wide array of human diseases including obesity, insulin resistance and the related metabolic syndrome, nonalcoholic steatohepatitis, cancer, chronic inflammatory diseases and infections, and neuroinflammatory processes have been linked to changes in the gut microbiome. In cases of alcohol use, the microbiome is a very likely target given that in human beings alcohol in the intestine has direct contact with components of the microbiome. In vitro studies have shown that alcohol has direct and selective effects on the growth of bacteria and intestinal overgrowth can produce ethanol that in turn may affect intestinal permeability.36Baraona E. Julkunen R. Tannenbaum L. et al.Role of intestinal bacterial overgrowth in ethanol production and metabolism in rats.Gastroenterology. 1986; 90: 103-110Abstract Full Text PDF PubMed Google Scholar Metagenomic analysis of alcohol-induced alteration in the intestinal microbiome showed that alcohol feeding in mice decreases the bacterial diversity and shifts the phylum representation over time.37Bull-Otterson L. Feng W. Kirpich I. et al.Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment.PLoS One. 2013; 8: e53028Crossref PubMed Scopus (347) Google Scholar Compared with pair-fed mice, in which the majority of bacteria were in the Bacteriodes and Firmicutes phylum, alcohol feeding dramatically increased the presence of Actinobacteria and increased the proportion of Firmicutes over altered Bacteriodes.37Bull-Otterson L. Feng W. Kirpich I. et al.Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment.PLoS One. 2013; 8: e53028Crossref PubMed Scopus (347) Google Scholar In another study in a mouse model of alcoholic liver disease, bacterial translocation was found before changes in the microbiome and the bacterial translocation was associated with reduced expression of the bactericidal c-type lectins, Reg3b, and Reg3g in the small intestine.38Yan A.W. Fouts D.E. Brandl J. et al.Enteric dysbiosis associated with a mouse model of alcoholic liver disease.Hepatology. 2011; 53: 96-105Crossref PubMed Scopus (520) Google Scholar Chronic alcohol also alters the metabolic composition in the gastrointestinal content, which changes the source of nutrition for microbes in the gastrointestinal tract.39Xie G. Zhong W. Zheng X. et al.Chronic ethanol consumption alters mammalian gastrointestinal content metabolites.J Proteome Res. 2013; 12: 3297-3306Crossref PubMed Scopus (93) Google Scholar For example, alcohol feeding resulted in a decrease in all amino acids and branched chain amino acids in the gut.39Xie G. Zhong W. Zheng X. et al.Chronic ethanol consumption alters mammalian gastrointestinal content metabolites.J Proteome Res. 2013; 12: 3297-3306Crossref PubMed Scopus (93) Google Scholar These deteriorations indicate that chronic alcohol use directly and indirectly changes the composition of the gut microbiota. Pathogen-associated molecular patterns (PAMPs) are sensed by pattern recognition receptors including TLRs, Nod-like receptors, helicase receptors, and others.40Szabo G. Bala S. Petrasek J. et al.Gut-liver axis and sensing microbes.Dig Dis. 2010; 28: 737-744Crossref PubMed Scopus (137) Google Scholar, 41Szabo G. Csak T. Inflammasomes in liver diseases.J Hepatol. 2012; 57: 642-654Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar The microbiome contains a broad variety of PAMPs and because of the intestinal barrier, these PAMPs do not reach the systemic circulation. The most studied gut-derived PAMP in the circulation is bacterial LPS, which is a component of the gram-negative bacterial wall. Many studies have shown that chronic alcohol consumption increases LPS levels in the portal as well as in the systemic circulation without entering the brain. This was found in human alcoholic patients with or without liver disease, as well as in rats and mice.23Rao R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease.Hepatology. 2009; 50: 638-644Crossref PubMed Scopus (331) Google Scholar, 33Bode C. Kugler V. Bode J.C. Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess.J Hepatol. 1987; 4: 8-14Abstract Full Text PDF PubMed Scopus (459) Google Scholar In mice, a single acute alcohol gavage can increase serum LPS levels, and administration of a 5% alcohol-containing diet also increases serum LPS levels in as early as 1 week.42Petrasek J. Bala S. Csak T. et al.IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice.J Clin Invest. 2012; 122: 3476-3489Crossref PubMed Scopus (466) Google Scholar A recent study showed that an acute alcohol binge in normal volunteers resulted in a rapid increase in serum LPS as well as in bacterial 16S DNA levels, suggesting disruption of the intestinal barrier function. In addition to LPS and 16S bacterial DNA, peptidoglycan, a component of gram-positive bacteria, also was detected in human alcoholic patients.43Leclercq S. De Saeger C. Delzenne N. et al.Role of inflammatory pathways, blood mononuclear cells, and gut-derived bacterial products in alcohol dependence.Biol Psychiatry. 2014; 76: 725-733Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar It also has been shown that TLR4- or CD14-deficient mice that have disruption of the LPS-receptor complex are protected from alcoholic liver disease.17Uesugi T. Froh M. Arteel G.E. et al.Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice.Hepatology. 2001; 34: 101-108Crossref PubMed Scopus (411) Google Scholar, 18Petrasek J. Mandrekar P. Szabo G. Toll-like receptors in the pathogenesis of alcoholic liver disease.Gastroenterol Res Pract. 2010; 2010 (Epub August 17, 2010)https://doi.org/10.1155/2010/710381Crossref PubMed Scopus (75) Google Scholar, 44Hritz I. Mandrekar P. Velayudham A. et al.The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88.Hepatology. 2008; 48: 1224-1231Crossref PubMed Scopus (320) Google Scholar Consistent with this, sterilization of the gut also attenuated alcohol-induced liver disease in animal models.45Adachi Y. Moore L.E. Bradford B.U. et al.Antibiotics prevent liver injury in rats following long-term exposure to ethanol.Gastroenterology. 1995; 108: 218-224Abstract Full Text PDF PubMed Scopus (595) Google Scholar Repeated engagement of TLR4/CD14 with LPS results in TLR tolerance in macrophages.46Medvedev A.E. Sabroe I. Hasday J.D. et al.Tolerance to microbial TLR ligands: molecular mechanisms and relevance to disease.J Endotoxin Res. 2006; 12: 133-150Crossref PubMed Scopus (173) Google Scholar, 47Morris M. Li L. Molecular mechanisms and pathological consequences of endotoxin tolerance and priming.Arch Immunol Ther Exp (Warsz). 2012; 60: 13-18Crossref PubMed Scopus (88) Google Scholar However, in the alcoholic liver environment with increased portal blood LPS, KCs and macrophages become sensitized to LPS,47Morris M. Li L. Molecular mechanisms and pathological consequences of endotoxin tolerance and priming.Arch Immunol Ther Exp (Warsz). 2012; 60: 13-18Crossref PubMed Scopus (88) Google Scholar leading to increased TNFα production.48Bala S. Marcos M. Kodys K. et al.Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor {alpha} (TNF{alpha}) production via increased mRNA half-life in alcoholic liver disease.J Biol Chem. 2011; 286: 1436-1444Crossref PubMed Scopus (326) Google Scholar, 49Kishore R. McMullen M.R. Cocuzzi E. et al.Lipopolysaccharide-mediated signal transduction: stabilization of TNF-alpha mRNA contributes to increased lipopolysaccharide-stimulated TNF-alpha production by Kupffer cells after chronic ethanol feeding.Comp Hepatol. 2004; 3: S31Crossref PubMed Google Scholar Activation of the TLR4-receptor complex by alcohol-induced LPS results in downstream activation of the nuclear factor-κB pathway and induction of proinflammatory cytokines and chemokines. Among those are TNFα and IL1ß, which have been shown to increase gut permeability, thereby potentially amplifying the alcohol-induced initial gut leakiness and liver disease process.50Yoseph B.P. Breed E. Overgaard C.E. et al.Chronic alcohol ingestion increases mortality and organ injury in a murine model of septic peritonitis.PLoS One. 2013; 8: e62792Crossref PubMed Scopus (42) Google Scholar Locally in the intestinal mucosa, chronic alcohol results in increased expression of TNFα an IL1ß.24Lippai D. Bala S. Catalano D. et al.MicroRNA-155 deficiency prevents alcohol-induced serum endotoxin increase and small bowel inflammation in mice.Alcohol Clin Exp Res. 2014; 38: 2217-2224Crossref PubMed Scopus (76) Google Scholar Recent reports have described that IL22 is a cytokine that regulates gut epithelia cells and immune functions. In a burn injury model, the addition of alcohol amplified reduction in IL22, which correlated with increased gut permeability. In the same study, IL22 administration prevented the increased gut permeability caused by the combined insult of alcohol plus burn injury.51Rendon J.L. Li X. Akhtar S. et al.Interleukin-22 modulates gut epithelial and immune barrier functions following acute alcohol exposure and burn injury.Shock. 2013; 39: 11-18Crossref PubMed Scopus (58) Google Scholar In another study, IL22 administration ameliorated alcoholic liver injury, raising the question of whether IL22 acts directly on the liver or via the gut–liver axis in ALD.52Ki S.H. Park O. Zheng M. et al.Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3.Hepatology. 2010; 52: 1291-1300Crossref PubMed Scopus (331) Google Scholar IL22 is produced by innate lymphoid cells (ILCs) that reside in the bowel wall.5Schnabl B. Brenner D.A. Interactions between the intestinal microbiome and liver diseases.Gastroenterology. 2014; 146: 1513-1524Abstract Full Text Full Text PDF PubMed Scopus (607) Google Scholar, 53Taube C. Tertilt C. Gyulveszi G. et al.IL-22 is produced by innate lymphoid cells and limits inflammation in allergic airway disease.PLoS One. 2011; 6: e21799Crossref PubMed Scopus (107) Google Scholar In the intestinal wall the interaction of immune cells is an important component in the maintenance of the host and microbiome balance. Recent studies have suggested that microbiota can dictate the cross-talk between macrophages and ILC3, and this promotes intestinal homeostasis.54Mortha A. Chudnovsk" @default.
• W2034801500 created "2016-06-24" @default.
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• W2034801500 date "2015-01-01" @default.
• W2034801500 modified "2023-10-15" @default.
• W2034801500 title "Gut–Liver Axis in Alcoholic Liver Disease" @default.
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• W2034801500 doi "https://doi.org/10.1053/j.gastro.2014.10.042" @default.
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