Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting

Alcohol use disorders are associated with altered stress responses, but the impact of stress or stress hormones on alcohol-associated tissue injury remain unknown. We evaluated the effects of chronic restraint stress on alcohol-induced gut barrier dysfunction and liver damage in mice. To determine whether corticosterone is the stress hormone associated with the stress-induced effects, we evaluated the effect of chronic corticosterone treatment on alcoholic tissue injury at the Gut-Liver-Brain (GLB) axis. Chronic restraint stress synergized alcohol-induced epithelial tight junction disruption and mucosal barrier dysfunction in the mouse intestine. These effects of stress on the gut were reproduced by corticosterone treatment. Corticosterone synergized alcohol-induced expression of inflammatory cytokines and chemokines in the colonic mucosa, and it potentiated the alcohol-induced endotoxemia and systemic inflammation. Corticosterone also potentiated alcohol-induced liver damage and neuroinflammation. Metagenomic analyses of 16S RNA from fecal samples indicated that corticosterone modulates alcohol-induced changes in the diversity and abundance of gut microbiota. In Caco-2 cell monolayers, corticosterone dose-dependently potentiated ethanol and acetaldehyde-induced tight junction disruption and barrier dysfunction. These data indicate that chronic stress and corticosterone exacerbate alcohol-induced mucosal barrier dysfunction, endotoxemia, and systemic alcohol responses. Corticosterone-mediated promotion of alcohol-induced intestinal epithelial barrier dysfunction and modulation of gut microbiota may play a crucial role in the mechanism of stress-induced promotion of alcohol-associated tissue injury at the GLB axis.

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“…Chronic alcohol use causes fatty liver and hepatitis 32 . We examined the potential influence of chronic stress on alcohol-induced liver injury.…”

Section: Resultsmentioning

confidence: 99%

Chronic stress and corticosterone exacerbate alcohol-induced tissue injury in the gut-liver-brain axis

Shukla

Meena

Dalal

et al. 2021

Sci Rep

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“…The early working model for ALD initiation demonstrated that portal circulation of the bacterial product lipopolysaccharide (LPS) from alcohol-induced gut leakage to liver-activated Kupffer cells (KCs) through LPS/Toll-like receptor (TLR) 4 signaling and subsequently produced inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), leading to alcoholic liver injury. [1][2][3] In recent years, emerging evidence from preclinical and clinical studies has suggested that new immunological mechanisms are involved in all stages of ALD, including immune response initiation, inflammatory reactions, and completed/unresolved repair. 4 In the early stage, inducers/sensors, including alcoholic hepatocyte death, cause an immune response in the liver.…”

Section: Introductionmentioning

confidence: 99%

Immunological mechanisms and therapeutic targets of fatty liver diseases

et al. 2020

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Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the two major types of chronic liver disease worldwide. Inflammatory processes play key roles in the pathogeneses of fatty liver diseases, and continuous inflammation promotes the progression of alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). Although both ALD and NAFLD are closely related to inflammation, their respective developmental mechanisms differ to some extent. Here, we review the roles of multiple immunological mechanisms and therapeutic targets related to the inflammation associated with fatty liver diseases and the differences in the progression of ASH and NASH. Multiple cell types in the liver, including macrophages, neutrophils, other immune cell types and hepatocytes, are involved in fatty liver disease inflammation. In addition, microRNAs (miRNAs), extracellular vesicles (EVs), and complement also contribute to the inflammatory process, as does intertissue crosstalk between the liver and the intestine, adipose tissue, and the nervous system. We point out that inflammation also plays important roles in promoting liver repair and controlling bacterial infections. Understanding the complex regulatory process of disrupted homeostasis during the development of fatty liver diseases may lead to the development of improved targeted therapeutic intervention strategies.

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“… 1 , 5 Chronic liver injury leading to HCC development is mainly caused by HBV and HCV infections, long-lasting alcohol abuse and non-alcoholic fatty liver disease (NAFLD). 1 , 2 , 10 , 11 With the systematic implementation of HBV vaccination and the advent of effective anti-HCV therapies, it is likely that NAFLD will become the dominant cause of HCC in the coming years. 2 …”

Section: Introductionmentioning

confidence: 99%

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

et al. 2020

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Summary Hepatocellular carcinoma (HCC) is a deadly tumour whose causative agents are generally well known, but whose pathogenesis remains poorly understood. Nevertheless, key genetic alterations are emerging from a heterogeneous molecular landscape, providing information on the tumorigenic process from initiation to progression. Among these molecular alterations, those that affect epigenetic processes are increasingly recognised as contributing to carcinogenesis from preneoplastic stages. The epigenetic machinery regulates gene expression through intertwined and partially characterised circuits involving chromatin remodelers, covalent DNA and histone modifications, and dedicated proteins reading these modifications. In this review, we summarise recent findings on HCC epigenetics, focusing mainly on changes in DNA and histone modifications and their carcinogenic implications. We also discuss the potential drugs that target epigenetic mechanisms for HCC treatment, either alone or in combination with current therapies, including immunotherapies.

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Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting

Cited by 148 publications

References 150 publications

Chronic stress and corticosterone exacerbate alcohol-induced tissue injury in the gut-liver-brain axis

Chronic stress and corticosterone exacerbate alcohol-induced tissue injury in the gut-liver-brain axis

Immunological mechanisms and therapeutic targets of fatty liver diseases

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

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