Host-Microbiome Interactions in Alcoholic Liver Disease

Chen, Peng; Schnabl, Bernd

doi:10.5009/gnl.2014.8.3.237

Cited by 69 publications

(54 citation statements)

References 44 publications

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“…Loss of intestinal barrier integrity and disturbed microbiota composition, as also observed in Mdr2 −/− mice, aggravate chronic liver diseases ranging from NAFLD,38 ALD49 as well as liver fibrosis50 and hepatocellular carcinoma 51…”

Section: Discussionmentioning

confidence: 99%

Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis

Liao¹,

Schneider

Galvez

et al. 2019

Gut

146

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ObjectiveThere is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut–liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2−/−) model resembling human primary sclerosing cholangitis (PSC).DesignMale Mdr2 −/−, Mdr2−/− crossed with hepatocyte-specific deletion of caspase-8 (Mdr2−/− /Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2−/− -associated intestinal dysbiosis was studied by microbiota transfer experiments.Results Mdr2−/− mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut–liver axis. Intestinal dysbiosis in Mdr2−/− mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2−/− microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature.ConclusionsMDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.

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Section: Discussionmentioning

confidence: 99%

Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis

Liao¹,

Schneider

Galvez

et al. 2019

Gut

146

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show abstract

“…[5][6][7] Moreover, the intake of ethanol disturbs the gut microbiota composition and increases bacterial endotoxin production. [8][9][10] Excessive exposure to endotoxins can cause inflammation in the gastrointestinal tract (e.g., colitis), and disruption in gut wall functions; this further accelerates the absorption of intestinal bacterial by-products, including endotoxins, into the blood. 10,11 Excessive absorption of endotoxins such as lipopolysaccharide (LPS) into the blood causes inflammation in the liver, and deteriorates non-alcoholic and alcoholic liver diseases including steatosis, hepatitis, and hepatic fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Lactobacillus plantarum LC27 and Bifidobacterium longum LC67 mitigate alcoholic steatosis in mice by inhibiting LPS-mediated NF-κB activation through restoration of the disturbed gut microbiota

Kim

Kwon

et al. 2018

Food Funct.

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Long-term exposure to ethanol simultaneously causes gastrointestinal inflammation, liver injury, and steatosis. In the present study, we investigated the effects of Bifidobacterium longum LC67, Lactobacillus plantarum LC27, and their mixture (LM) against ethanol-induced steatosis in mice. Exposure to ethanol caused liver damage: it increased ALT, AST, TG, TC, and lipopolysaccharide levels in the blood and induced NF-κB activation in the liver. Oral administration of LC27, LC67, or LM in mice reduced ethanolinduced ALT, AST, TG, and TC levels in the blood and liver. These also suppressed ethanol-induced NF-κB activation and α-smooth muscle actin expression in the liver and increased ethanol-suppressed AMPK activation. Treatment with LC27, LC67, or LM increased ethanol-suppressed alcohol dehydrogenase and acetaldehyde dehydrogenase activities in the liver, as well as tight junction protein expression in the liver and colon. Moreover, treatment with LC27, LC67, or LM restored the ethanol-disturbed gut microbiota composition, such as the increased population of Proteobacteria, and inhibited fecal and blood lipopolysaccharide levels. These inhibited NF-κB activation and increased tight junction protein expression in ethanol-or lipopolysaccharide-stimulated Caco-2 cells. These findings suggest that LC27, LC67, and LM can alleviate alcoholic steatosis by inhibiting LPS-mediated NF-κB activation through restoration of the disturbed gut microbiota.

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“…Microbial geni involved in ethanol oxidation have been identified as gram-positive Ruminococcus , Collinsella , Coriobacterium, Bifidobacterium and gram-negative Prevotella (103). Escherichia coli has also been linked to the accumulation of acetaldehyde in the intestinal lumen (104). Due to the ensuing oxidative stress caused by chronic alcohol exposure, obligate anaerobes are less likely to prevail than other species that are more tolerant to the microenvironment, such as Proteobaceria ; a species linked to inflammation (105).…”

Section: Microbial Co-exposure and Mechanisms Of Colorectal Cancermentioning

confidence: 99%

Environmental Influences in the Etiology of Colorectal Cancer: the Premise of Metabolomics

et al. 2017

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Purpose of Review In this review we discuss how environmental exposures predominate the etiology of colorectal cancer (CRC). With CRC being a personalized disease influenced by genes and environment, our goal was to explore the role metabolomics can play in identifying exposures, assessing the interplay between co-exposures, and the development of personalized therapeutic interventions. Recent Findings Approximately 10 % of CRC cases can be explained by germ-line mutations, whereas the prevailing majority are caused by an initiating exposure event occurring decades prior to diagnosis. Recent research has shown that dietary metabolites are linked to a procarcinogenic or protective environment in the colon which is modulated by the microbiome. In addition, excessive alcohol has been shown to increase the risk of CRC and is dependent on diet (folate), the response of microbiome, and genetic polymorphisms within the folate and alcohol metabolic pathways. Metabolomics can not only be used to identify this modulation of host metabolism, which could affect the progression of the tumors but also response to targeted therapeutics. Summary This review highlights the current understanding of the multifaceted etiology and mechanisms of CRC development but also highlights where the field of metabolomics can contribute to a greater understanding of environmental exposure in CRC.

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Host-Microbiome Interactions in Alcoholic Liver Disease

Cited by 69 publications

References 44 publications

Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis

Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis

Lactobacillus plantarum LC27 and Bifidobacterium longum LC67 mitigate alcoholic steatosis in mice by inhibiting LPS-mediated NF-κB activation through restoration of the disturbed gut microbiota

Environmental Influences in the Etiology of Colorectal Cancer: the Premise of Metabolomics

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