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The Gut-liver Axis in Immune Remodeling: New insight into Liver Diseases.

ABSTRACT: The gut microbiota consists of a dynamic multispecies community of bacteria, fungi, archaea, and protozoans, playing a fundamental role in the induction, training, and function of the host immune system. The liver is anatomically and physiologically linked to the gut microbiota via enterohepatic circulation, specifically receiving intestine-derived blood through the portal vein. The gut microbiota is crucial for maintaining immune homeostasis of the gut-liver axis. A shift in gut microbiota composition can result in activation of the mucosal immune response causing homeostasis imbalance. This imbalance results in translocation of bacteria and migration of immune cells to the liver, which is related to inflammation-mediated liver injury and tumor progression. In this review, we outline the role of the gut microbiota in modulating host immunity and summarize novel findings and recent advances in immune-based therapeutics associated with the gut-liver axis. Moving forward, a deep understanding of the microbiome-immune-liver axis will provide insight into the basic mechanisms of gut microbiota dysbiosis affecting liver diseases.

SUBMITTER: Yang X

PROVIDER: S-EPMC7378637 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Gut-liver Axis in Immune Remodeling: New insight into Liver Diseases.

Yang Xinyu X Lu Di D Zhuo Jianyong J Lin Zuyuan Z Yang Modan M Xu Xiao X

International journal of biological sciences 20200623 13

The gut microbiota consists of a dynamic multispecies community of bacteria, fungi, archaea, and protozoans, playing a fundamental role in the induction, training, and function of the host immune system. The liver is anatomically and physiologically linked to the gut microbiota via enterohepatic circulation, specifically receiving intestine-derived blood through the portal vein. The gut microbiota is crucial for maintaining immune homeostasis of the gut-liver axis. A shift in gut microbiota comp ...[more]

PMID: 32760203

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Project description:Nonalcoholic fatty liver disease (NAFLD) includes simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The gut-derived endotoxin plays an essential role in the pathophysiological development and progression of NAFLD. By using rat models of choline-deficient/L-amino acid-defined (CDAA)-diet-induced NAFLD, we examined whether MIYAIRI 588--a butyrate-producing probiotic--prevents the progression of pathophysiological changes from steatosis to hepatocarcinogenesis. In vivo experiments showed that treatment with MIYAIRI 588 reduced CDAA-diet-induced hepatic lipid deposition and significantly improved the triglyceride content, insulin resistance, serum endotoxin levels, and hepatic inflammatory indexes. We also found that MIYAIRI 588 substantially increased the activation of hepatic adenosine 5'-monophosphate-activated protein kinase (AMPK) and AKT and the expression of lipogenesis- or lipolysis-related proteins. MIYAIRI 588 also improved CDAA-diet-induced delocalization and substantially decreased the expression of the tight-junction proteins intestinal zonula occluden-1 and occludin in CDAA-diet-fed rats. Further, the MIYAIRI 588-treated rats also showed remarkable induction of nuclear factor erythoid 2-related factor 2 (Nrf2) and its targeted antioxidative enzymes, which suppressed hepatic oxidative stress. In vitro studies revealed that treatment with sodium butyrate (NaB) also activated AMPK and AKT and enhanced Nrf2 expression by precluding ubiquitination, thereby increasing the half-life of the Nrf2 protein. Pharmacological studies and siRNA knockdown experiments showed that NaB-mediated AMPK activation induced the phosphorylation and nuclear translocation of Sirtuin 1, leading to the increased assembly of mammalian TOR complex 2 and phosphorylation of AKT at Ser473 and subsequent induction of Nrf2 expression and activation. These favorable changes caused an obvious decrease in hepatic fibrous deposition, GST-P-positive foci development, and hepatocarcinogenesis. Our data clearly established that the probiotic MIYAIRI 588 has beneficial effects in the prevention of NAFLD progression.

Project description:The gut-liver axis covers the bidirectional communication between the gut and the liver, and thus includes signals from liver-to-gut (e.g., bile acids, immunoglobulins) and from gut-to-liver (e.g., nutrients, microbiota-derived products, and recirculating bile acids). In a healthy individual, liver homeostasis is tightly controlled by the mostly tolerogenic liver resident macrophages, the Kupffer cells, capturing the gut-derived antigens from the blood circulation. However, disturbances of the gut-liver axis have been associated to the progression of varying chronic liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and primary sclerosing cholangitis. Notably, changes of the gut microbiome, or intestinal dysbiosis, combined with increased intestinal permeability, leads to the translocation of gut-derived bacteria or their metabolites into the portal vein. In the context of concomitant or subsequent liver inflammation, the liver is then infiltrated by responsive immune cells (e.g., monocytes, neutrophils, lymphoid, or dendritic cells), and microbiota-derived products may provoke or exacerbate innate immune responses, hence perpetuating liver inflammation and fibrosis, and potentiating the risks of developing cirrhosis. Similarly, food derived antigens, bile acids, danger-, and pathogen-associated molecular patterns are able to reshape the liver immune microenvironment. Immune cell intracellular signaling components, such as inflammasome activation, toll-like receptor or nucleotide-binding oligomerization domain-like receptors signaling, are potent targets of interest for the modulation of the immune response. This review describes the current understanding of the cellular landscape and molecular pathways involved in the gut-liver axis and implicated in chronic liver disease progression. We also provide an overview of innovative therapeutic approaches and current clinical trials aiming at targeting the gut-liver axis for the treatment of patients with chronic liver and/or intestinal diseases.

Dataset Information

The Gut-liver Axis in Immune Remodeling: New insight into Liver Diseases.

Publications

The Gut-liver Axis in Immune Remodeling: New insight into Liver Diseases.

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