Enteric dysbiosis associated with a mouse model of alcoholic liver disease

Yan, Arthur W.; Fouts, Derrick E.; Brandl, Johannes; Stärkel, Peter; Torralba, Manolito; Schott, Eckart; Tsukamoto, Hide; Nelson, Karen E.; Brenner, David A.; Schnabl, Bernd

doi:10.1002/hep.24018

Cited by 694 publications

(772 citation statements)

References 82 publications

Supporting

Mentioning

680

Contrasting

Unclassified

Order By: Relevance

“…Preclinical studies have shown that chronic ethanol administration induces in rats a dysbiosis (45), and in mice a decrease in the level of Ruminococcaceae (46), or a decrease in the level of Firmicutes and an increase in Bacteroidetes (47). In humans, few studies have evaluated the gut microbiome of AD subjects and never in relation to gut permeability.…”

Section: Effect Of Alcohol Withdrawal On Gut-microbiota Compositionmentioning

confidence: 99%

Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity

Leclercq

Matamoros

Cani

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

740

645

View full text Add to dashboard Cite

Alcohol dependence has traditionally been considered a brain disorder. Alteration in the composition of the gut microbiota has recently been shown to be present in psychiatric disorders, which suggests the possibility of gut-to-brain interactions in the development of alcohol dependence. The aim of the present study was to explore whether changes in gut permeability are linked to gut-microbiota composition and activity in alcohol-dependent subjects. We also investigated whether gut dysfunction is associated with the psychological symptoms of alcohol dependence. Finally, we tested the reversibility of the biological and behavioral parameters after a short-term detoxification program. We found that some, but not all, alcohol-dependent subjects developed gut leakiness, which was associated with higher scores of depression, anxiety, and alcohol craving after 3 wk of abstinence, which may be important psychological factors of relapse. Moreover, subjects with increased gut permeability also had altered composition and activity of the gut microbiota. These results suggest the existence of a gut-brain axis in alcohol dependence, which implicates the gut microbiota as an actor in the gut barrier and in behavioral disorders. Thus, the gut microbiota seems to be a previously unidentified target in the management of alcohol dependence.alcohol dependence | gut permeability | gut microbiota | gut-brain axis | behavior

show abstract

Section: Effect Of Alcohol Withdrawal On Gut-microbiota Compositionmentioning

confidence: 99%

Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity

Leclercq

Matamoros

Cani

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

740

645

View full text Add to dashboard Cite

show abstract

“…Recent data show that OPN binds lipopolysaccharide (LPS) and protects against early alcohol-induced liver injury by blocking the TNF-α effects in the liver [137] . Furthermore, OPN is reported to be a downstream effector of the Hedgehog pathway, which modulates fibrosis and is involved in peculiar aspects of hepatic carcinogenesis [138] .…”

Section: Mechanism Of Alcohol-induced Fibrogenesismentioning

confidence: 99%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

413

339

View full text Add to dashboard Cite

Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility. Key words: Alcohol metabolism; Acetaldehyde; Reactive oxygen species; Alcoholic liver disease; Protein adducts; Hepatic stellate cells; Liver fibrosis; CYP2E1Core tip: The goal of this article is to review the mechanisms of alcohol-mediated toxicity in parenchymal and non-parenchymal cells of the liver. Specifically, we highlight the effect of oxidative ethanol metabolites such as acetaldehyde and reactive oxygen species in the development of fat accumulation, fibrosis and deranged immune response.Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism.

show abstract

“…Multiple studies in animal models of NAFLD and ALD have shown a clear association between disease and dysbiosis (44,45). Additionally, there is evidence that the microbiome influences progression of NAFLD, ALD, and viral hepatitis to end-stage liver disease in humans (46,47), highlighting dysbiosis as a possible common denominator in these diseases.…”

Section: Gut Dysbiosismentioning

confidence: 99%