Ethanol‐mediated suppression of <scp>IL</scp>‐37 licenses alcoholic liver disease

Grabherr, Felix; Grander, Christoph; Adolph, Timon E.; Wieser, Verena; Mayr, Lisa; Enrich, Barbara; Macheiner, S; Sangineto, Moris; Reiter, Andreas; Viveiros, André; Zoller, Heinz; Bufler, Philip; Moschen, Alexander R.; Dinarello, Charles A.; Tilg, Herbert

doi:10.1111/liv.13642

Cited by 18 publications

(17 citation statements)

References 55 publications

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“…8- to 10-week-old female wild-type (C57BL/6) mice were fed with a Lieber-DeCarli diet containing up to 5% alcohol for 15 days (EtOH-fed) or Lieber-DeCarli diet alone (pair-fed), as shown in Figure 1a and previously described. 33 , 53 …”

Section: Methodsmentioning

confidence: 99%

Recovery of Bacteroides thetaiotaomicron ameliorates hepatic steatosis in experimental alcohol-related liver disease

et al. 2022

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Alcohol-related liver disease (ALD) is a major cause of liver disease and represents a global burden, as treatment options are scarce. Whereas 90% of ethanol abusers develop alcoholic fatty liver disease (AFLD), only a minority evolves to steatohepatitis and cirrhosis. Alcohol increases lipogenesis and suppresses lipid-oxidation implying steatosis, although the key role of intestinal barrier integrity and microbiota in ALD has recently emerged. Bacteroides thetaiotaomicron ( Bt ) is a prominent member of human and murine intestinal microbiota, and plays important functions in metabolism, gut immunity, and mucosal barrier. We aimed to investigate the role of Bt in the genesis of ethanol-induced liver steatosis. Bt DNA was measured in feces of wild-type mice receiving a Lieber-DeCarli diet supplemented with an increase in alcohol concentration. In a second step, ethanol-fed mice were orally treated with living Bt , followed by analysis of intestinal homeostasis and histological and biochemical alterations in the liver. Alcohol feeding reduced Bt abundance, which was preserved by Bt oral supplementation. Bt -treated mice displayed lower hepatic steatosis and triglyceride content. Bt restored mucosal barrier and reduced LPS translocation by enhancing mucus thickness and production of Mucin2. Furthermore, Bt up-regulated Glucagon-like peptide-1 (GLP-1) expression and restored ethanol-induced Fibroblast growth factor 15 (FGF15) down-regulation. Lipid metabolism was consequently affected as Bt administration reduced fatty acid synthesis (FA) and improved FA oxidation and lipid exportation. Moreover, treatment with Bt preserved the mitochondrial fitness and redox state in alcohol-fed mice. In conclusion, recovery of ethanol-induced Bt depletion by oral supplementation was associated with restored intestinal homeostasis and ameliorated experimental ALD. Bt could serve as a novel probiotic to treat ALD in the future.

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Section: Methodsmentioning

confidence: 99%

Recovery of Bacteroides thetaiotaomicron ameliorates hepatic steatosis in experimental alcohol-related liver disease

et al. 2022

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“…On the other hand, IL-37 has been associated with anti-inflammatory effects via IL-18Rα and IL-1R8 expression. In liver samples of ASH subjects, IL-37 expression was substantially reduced when compared to non-alcoholic fatty liver disease subjects [45] . An in vivo system in wild-type mice suggested that hepatic IL-37 expression was suppressed by ethanol through the administration of human recombinant IL-37 followed by oral gavage of an ethanol shot in those animals [45] .…”

Section: Mechanisms Involved In Hcc Developmentmentioning

confidence: 86%

“…In liver samples of ASH subjects, IL-37 expression was substantially reduced when compared to non-alcoholic fatty liver disease subjects [45] . An in vivo system in wild-type mice suggested that hepatic IL-37 expression was suppressed by ethanol through the administration of human recombinant IL-37 followed by oral gavage of an ethanol shot in those animals [45] . This is important since HCC clinical specimens have shown that decreased expression of IL-37 is negatively correlated with tumor size and positively associated with better overall survival and disease-free survival via the induction of tumor-infiltrating CD571 natural killer cells [46] .…”

Section: Mechanisms Involved In Hcc Developmentmentioning

confidence: 86%

The mechanism of dysbiosis in alcoholic liver disease leading to liver cancer

Méndez-Sánchez

Valencia-Rodríguez

Vera-Barajas

et al. 2020

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Currently, alcoholic liver disease (ALD) is one of the most prevalent chronic liver diseases worldwide, representing one of the main etiologies of cirrhosis and hepatocellular carcinoma (HCC). Although we do not know the exact mechanisms by which only a selected group of patients with ALD progress to the final stage of HCC, the role of the gut microbiota within the progression to HCC has been intensively studied in recent years. To date, we know that alcohol-induced gut dysbiosis is an important feature of ALD with important repercussions on the severity of this disease. In essence, an increased metabolism of ethanol in the gut induced by an excessive alcohol consumption promotes gut dysfunction and bacterial overgrowth, setting a leaky gut. This causes the translocation of bacteria, endotoxins, and ethanol metabolites across the enterohepatic circulation reaching the liver, where the recognition of the pathogen-associated molecular patterns via specific Toll-like receptors of liver cells will induce the activation of the nuclear factor kappa-B pathway, which releases pro-inflammatory cytokines and chemokines. In addition, the mitogenic activity of hepatocytes will be promoted and cellular apoptosis will be inhibited, resulting in the development of HCC. In this context, it is not surprising that microbiota-regulating drugs have proven effectiveness in prolonging the overall survival of patients with HCC, making attractive the implementation of these drugs as co-adjuvant for HCC treatment.

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“…Consistent with the murine results, patients with alcoholic steatohepatitis showed decreased expression of IL-37 in the liver compared to NAFLD patients. 195 In chronic liver diseases, such as ASH and NASH, fibrosis is characterized by the deposition of extracellular matrix (ECM), which contributes to organ failure. Gieling et al highlighted the role of IL-1 in the activation of HSCs, enabling the transition from liver injury to fibrosis.…”

Section: Il-1 Family Cytokinesmentioning

confidence: 99%

Immunopathobiology and therapeutic targets related to cytokines in liver diseases

Hwang

Ahmed

et al. 2020

Cell Mol Immunol

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Chronic liver injury with any etiology can progress to fibrosis and the end-stage diseases cirrhosis and hepatocellular carcinoma. The progression of liver disease is controlled by a variety of factors, including liver injury, inflammatory cells, inflammatory mediators, cytokines, and the gut microbiome. In the current review, we discuss recent data on a large number of cytokines that play important roles in regulating liver injury, inflammation, fibrosis, and regeneration, with a focus on interferons and T helper (Th) 1, Th2, Th9, Th17, interleukin (IL)-1 family, IL-6 family, and IL-20 family cytokines. Hepatocytes can also produce certain cytokines (such as IL-7, IL-11, and IL-33), and the functions of these cytokines in the liver are briefly summarized. Several cytokines have great therapeutic potential, and some are currently being tested as therapeutic targets in clinical trials for the treatment of liver diseases, which are also described.

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Ethanol‐mediated suppression of IL‐37 licenses alcoholic liver disease

Abstract: We provide evidence for an exogenous noxae that suppresses Interleukin 37 expression which limits its anti-inflammatory effects in alcoholic liver disease.

Cited by 18 publications

References 55 publications

Recovery of Bacteroides thetaiotaomicron ameliorates hepatic steatosis in experimental alcohol-related liver disease

Recovery of Bacteroides thetaiotaomicron ameliorates hepatic steatosis in experimental alcohol-related liver disease

The mechanism of dysbiosis in alcoholic liver disease leading to liver cancer

Immunopathobiology and therapeutic targets related to cytokines in liver diseases

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