Mouse model of chronic and binge ethanol feeding (the NIAAA model)

Alcoholic liver disease (ALD) is a leading cause of liver-related morbidity and mortality worldwide. There is no effective treatment to prevent the disease progression. Magnesium isoglycyrrhizinate (MgIG) showed potent anti-inflammatory, antioxidant, and hepatoprotective activities and was used for treating liver diseases in Asia. In this study, we examined whether MgIG could protect mice against alcohol-induced liver injury. The newly developed chronic plus binge ethanol feeding model was used to study the role of MgIG in ALD. Serum liver enzyme levels, H&E staining, immunohistochemical staining, flow cytometric analysis, and real-time PCR were used to evaluate the liver injury and inflammation. We showed that MgIG markedly ameliorated chronic plus binge ethanol feeding liver injury, as shown by decreased serum alanine transaminase and aspartate aminotransferase levels and reduced neutrophil infiltration. The reason may be attributed to the reduced expression of proinflammatory cytokines and chemokines with the treatment of MgIG. The hepatoprotective effect of MgIG was associated with suppression of neutrophil ROS production as well as hepatocellular oxidative stress. MgIG may play a critical role in protecting against chronic plus binge ethanol feeding-induced liver injury by regulating neutrophil activity and hepatic oxidative stress.

Download Full-text

TLR2 and TLR9 contribute to alcohol-mediated liver injury through induction of CXCL1 and neutrophil infiltration

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00031.2015 ◽

2015 ◽

Vol 309 (1) ◽

pp. G30-G41 ◽

Cited By ~ 63

Author(s):

Yoon Seok Roh ◽

Bi Zhang ◽

Rohit Loomba ◽

Ekihiro Seki

Keyword(s):

Liver Injury ◽

Alcoholic Hepatitis ◽

Early Stage ◽

Neutrophil Infiltration ◽

Wild Type ◽

Ethanol Feeding ◽

Binge Ethanol ◽

Deficient Mice ◽

Cxcl1 Expression

Although previous studies reported the involvement of the TLR4-TRIF pathway in alcohol-induced liver injury, the role of TLR2 and TLR9 signaling in alcohol-mediated neutrophil infiltration and liver injury has not been elucidated. Since alcohol binge drinking is recognized to induce more severe form of alcohol liver disease, we used a chronic-binge ethanol-feeding model as a mouse model for early stage of alcoholic hepatitis. Whereas a chronic-binge ethanol feeding induced alcohol-mediated liver injury in wild-type mice, TLR2- and TLR9-deficient mice showed reduced liver injury. Induction of neutrophil-recruiting chemokines, including Cxcl1, Cxcl2, and Cxcl5, and hepatic neutrophil infiltration were increased in wild-type mice, but not in TLR2- and TLR9-deficient mice. In vivo depletion of Kupffer cells (KCs) by liposomal clodronate reduced liver injury and the expression of Il1b, but not Cxcl1, Cxcl2, and Cxcl5, suggesting that KCs are partly associated with liver injury, but not neutrophil recruitment, in a chronic-binge ethanol-feeding model. Notably, hepatocytes and hepatic stellate cells (HSCs) produce high amounts of CXCL1 in ethanol-treated mice. The treatment with TLR2 and TLR9 ligands synergistically upregulated CXCL1 expression in hepatocytes. Moreover, the inhibitors for CXCR2, a receptor for CXCL1, and MyD88 suppressed neutrophil infiltration and liver injury induced by chronic-binge ethanol treatment. Consistent with the above findings, hepatic CXCL1 expression was highly upregulated in patients with alcoholic hepatitis. In a chronic-binge ethanol-feeding model, the TLR2 and TLR9-dependent MyD88-dependent pathway mediates CXCL1 production in hepatocytes and HSCs; the CXCL1 then promotes neutrophil infiltration into the liver via CXCR2, resulting in the development of alcohol-mediated liver injury.

Download Full-text

NLRP6 Inflammasome Modulates Disease Progression in a Chronic-Plus-Binge Mouse Model of Alcoholic Liver Disease

Cells ◽

10.3390/cells11020182 ◽

2022 ◽

Vol 11 (2) ◽

pp. 182

Author(s):

Rebecca Elena Mainz ◽

Stefanie Albers ◽

Madhuri Haque ◽

Roland Sonntag ◽

Nicole Simone Treichel ◽

...

Keyword(s):

Liver Disease ◽

Mouse Model ◽

Alcoholic Liver Disease ◽

Immune Cell ◽

Liver Steatosis ◽

Neutrophil Infiltration ◽

Ethanol Administration ◽

Intestinal Homeostasis ◽

Binge Ethanol

A considerable percentage of the population is affected by alcoholic liver disease (ALD). It is characterized by inflammatory signals from the liver and other organs, such as the intestine. The NLR family pyrin domain containing 6 (NLRP6) inflammasome complex is one of the most important inflammatory mediators. The aim of this study was to evaluate a novel mouse model for ALD characterized by 8-week chronic-plus-binge ethanol administration and to investigate the role of NLRP6 inflammasome for intestinal homeostasis and ALD progression using Nlrp6-/- mice. We showed that chronic-plus-binge ethanol administration triggers hepatic steatosis, injury, and neutrophil infiltration. Furthermore, we discovered significant changes of intestinal microbial communities, including increased relative abundances of bacteria within the phyla Bacteroidota and Campilobacterota, as well as reduced Firmicutes. In this ALD model, inhibiting NLRP6 signaling had no effect on liver steatosis or damage, but had a minor impact on intestinal homeostasis via affecting intestinal epithelium function and gut microbiota. Surprisingly, Nlrp6 loss resulted in significantly decreased hepatic immune cell infiltration. As a result, our novel mouse model encompasses several aspects of human ALD, such as intestinal dysbiosis. Interfering with NLRP6 inflammasome activity reduced hepatic immune cell recruitment, indicating a disease-aggravating role of NLRP6 during ALD.

Download Full-text

Dietary Synbiotic Supplementation Protects Barrier Integrity of Hepatocytes and Liver Sinusoidal Endothelium in a Mouse Model of Chronic-Binge Ethanol Exposure

Nutrients ◽

10.3390/nu12020373 ◽

2020 ◽

Vol 12 (2) ◽

pp. 373 ◽

Cited By ~ 3

Author(s):

Yingchun Han ◽

Bryan Glueck ◽

David Shapiro ◽

Aaron Miller ◽

Sanjoy Roychowdhury ◽

...

Keyword(s):

Mouse Model ◽

Ethanol Exposure ◽

Endothelial Barrier ◽

Saline Control ◽

Control Group ◽

Liver Sinusoidal Endothelial Cells ◽

Microbial Composition ◽

Barrier Integrity ◽

Synbiotic Supplementation ◽

Binge Ethanol

Alcohol overconsumption disrupts the gut microbiota and intestinal barrier, which decreases the production of beneficial microbial metabolic byproducts and allows for translocation of pathogenic bacterial-derived byproducts into the portal-hepatic circulation. As ethanol is known to damage liver sinusoidal endothelial cells (LSEC), here we evaluated dietary supplementation with a previously studied synbiotic on gut microbial composition, and hepatocyte and LSEC integrity in mice exposed to ethanol. We tested a chronic-binge ethanol feeding mouse model in which C57BL/6 female mice were fed ethanol (5% vol/vol) for 10 days and provided a single ethanol gavage (5 g/kg body weight) on day 11, 6 h before euthanasia. An ethanol-treatment group also received oral supplementation daily with a synbiotic; and an ethanol-control group received saline. Control mice were pair-fed and isocalorically substituted maltose dextran for ethanol over the entire exposure period; they received a saline gavage daily. Ethanol exposure decreased gut microbial abundance and diversity. This was linked with diminished expression of adherens junction proteins in hepatocytes and dysregulated expression of receptors for advanced glycation end-products; and this coincided with reduced expression of endothelial barrier proteins. Synbiotic supplementation mitigated these effects. These results demonstrate synbiotic supplementation, as a means to modulate ethanol-induced gut dysbiosis, is effective in attenuating injury to hepatocyte and liver endothelial barrier integrity, highlighting a link between the gut microbiome and early stages of acute liver injury in ethanol-exposed mice.

Download Full-text

Crosstalk between gut microbiota and host lipid metabolism in a mouse model of alcoholic liver injury by chronic baijiu or ethanol feeding

Food & Function ◽

10.1039/d1fo02892h ◽

2022 ◽

Author(s):

Cheng Fang ◽

Qingwu Zhou ◽

Qingyang Liu ◽

Wei Jia ◽

Yan Xu

Keyword(s):

Lipid Metabolism ◽

Liver Injury ◽

Mouse Model ◽

Gut Microbiota ◽

Alcoholic Beverage ◽

Alcoholic Liver Injury ◽

Ethanol Feeding

This study demonstrates that compounds in baijiu, a traditional Chinese alcoholic beverage, can attenuate the development of ethanol-induced liver injury by regulating the crosstalk between gut microbiota and host lipid metabolism.

Download Full-text

Molecular Changes during Neurodevelopment following Second-Trimester Binge Ethanol Exposure in a Mouse Model of Fetal Alcohol Spectrum Disorder: From Immediate Effects to Long-Term Adaptation

Developmental Neuroscience ◽

10.1159/000357496 ◽

2014 ◽

Vol 36 (1) ◽

pp. 29-43 ◽

Cited By ~ 24

Author(s):

Katarzyna Mantha ◽

Benjamin I. Laufer ◽

Shiva M. Singh

Keyword(s):

Mouse Model ◽

Fetal Alcohol Spectrum Disorder ◽

Ethanol Exposure ◽

Second Trimester ◽

Fetal Alcohol ◽

Molecular Changes ◽

Binge Ethanol Exposure ◽

Fetal Alcohol Spectrum ◽

Binge Ethanol

Download Full-text

Animals Models of Gastrointestinal and Liver Diseases. Animal models of alcohol-induced liver disease: pathophysiology, translational relevance, and challenges

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00041.2014 ◽

2014 ◽

Vol 306 (10) ◽

pp. G819-G823 ◽

Cited By ~ 79

Author(s):

Stephanie Mathews ◽

Mingjiang Xu ◽

Hua Wang ◽

Adeline Bertola ◽

Bin Gao

Keyword(s):

Liver Disease ◽

Liver Injury ◽

Neutrophil Infiltration ◽

Alcoholic Liver Injury ◽

Drinking Patterns ◽

Excessive Alcohol Consumption ◽

Ethanol Feeding ◽

History Of ◽

Excessive Alcohol ◽

Binge Ethanol

Over the last four decades, chronic ethanol feeding studies in rodents using either ad libitum feeding or intragastric infusion models have significantly enhanced our understanding of the pathogenesis of alcoholic liver disease (ALD). Recently, we developed a chronic plus binge alcohol feeding model in mice that is similar to the drinking patterns of many alcoholic hepatitis patients: a history of chronic drinking and recent excessive alcohol consumption. Chronic+binge ethanol feeding synergistically induced steatosis, liver injury, and neutrophil infiltration in mice, which may be useful for the study of early alcoholic liver injury and inflammation. Using this chronic+binge model, researchers have begun to identify novel mechanisms that participate in the pathogenesis of alcoholic liver injury, thereby revealing novel therapeutic targets. In this review article, we briefly discuss several mouse models of ALD with a focus on the chronic+binge ethanol feeding model.

Download Full-text

Engineered Butyrate-producing Bacillus Subtilis Alleviated Ethanol-induced Intestinal and Liver Damage in Mice

10.21203/rs.3.rs-97812/v1 ◽

2020 ◽

Author(s):

Xing Lu ◽

Meiqi Zhao ◽

Yitao Duan ◽

Fengmei Wang ◽

Chuanai Chen

Keyword(s):

Bacillus Subtilis ◽

Barrier Function ◽

Circulatory System ◽

Intestinal Barrier ◽

Ethanol Exposure ◽

Intestinal Barrier Function ◽

Intestinal Dysbiosis ◽

Ethanol Feeding ◽

And Function ◽

Binge Ethanol

Abstract Ethanol-induced intestinal and liver injury are closely associated with intestinal dysbiosis and altered short-chain fatty acid (SCFA) metabolites which is crucial for intestinal health. Bacillus subtilis (BS) strains with biotherapeutic potential can benefit the host through maintaining intestinal homeostasis and regulating systematic immunity via producing small molecules, although these molecules do not include butyrate. To combine the advantages of butyrate and BS, we evaluated the bioactivity of an engineered butyrate-producing Bacillus subtilis (BPBS) strain against ethanol exposure in a chronic-binge ethanol feeding mouse model. Our findings suggested that prophylactic BPBS supplementation restored eubiosis of the gut microbiota and intestinal barrier function, which obviously reduced bacterial translocation of microbial products especially lipopolysaccharide (LPS) to the circulatory system. Additionally, the decrease of serum LPS is responsible for the relief of hepatic inflammation via the Toll-like receptor 4 (TLR4) pathway, resulting in improved hepatic structure and function. Collectively, these results demonstrated that engineered BPBS intervention imparted novel hepatoprotective functions by improving intestinal barrier function and reducing systematic inflammation under ethanol exposure, as well as paving the way for further exploration of engineered probiotics in improving human health care.

Download Full-text