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MicroRNA-141 ameliorates alcoholic hepatitis‑induced intestinal injury and intestinal endotoxemia partially via a TLR4-dependent mechanism.

ABSTRACT: Alcoholic hepatitis (AH) is a fatal inflammatory syndrome with no effective treatments. Intestinal injury and intestinal endotoxemia (IETM) contribute greatly in the development of AH. MicroRNAs (miRNAs/miRs) have been reported to affect intestinal injury. The present study aims to investigate the role of miR‑141 in intestinal injury and IETM of AH. An AH model was successfully established in mice and they were the injected with a series of miR‑141 mimic, miR‑141 inhibitor or toll like receptor 4 monoclonal antibody (TLR4mAb; an inhibitor of the Toll‑like receptor TLR pathway). After that, the intestinal tissues and intestinal epithelial cells were isolated from differently treated AH mice. The expression of miR‑141 and TLR pathway‑associated genes and the levels of inflammatory factors were determined. Furthermore, a target prediction program and a luciferase reporter assay were employed to examine whether miR‑141 targets TLR4. Finally, MTT and transwell assays were carried out to detect cell viability and cell permeability. Intestinal tissues from AH mice treated with miR‑141 mimic or TLR4mAb exhibited lower levels of inflammatory factors and reduced expression of the TLR pathway‑associated genes, suggesting a decreased inflammatory response as well as inactivation of the TLR pathway by miR‑141. The luciferase reporter assay suggested that miR‑141 negatively regulated TLR4. Intestinal epithelial cells treated with miR‑141 mimic or TLR4mAb demonstrated enhanced viability and reduced permeability. Opposite results were observed in AH mice treated with a miR‑141 inhibitor. Collectively, the results of the present study demonstrated that miR‑141 could ameliorate intestinal injury and repress the progression of IETM through targeting TLR4 and inhibiting the TLR pathway.

SUBMITTER: Qian WH

PROVIDER: S-EPMC6605973 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAlcoholic fatty liver disease (AFLD) is characterized by hepatic steatosis and carries an elevated risk of cirrhosis and hepatocellular carcinoma. However, the mechanism of AFLD has not been elucidated thoroughly, and there are still no efficient therapies in clinic. Notably, butyrate, one kind of short-chain fatty acids produced by gut microbiota, has been shown to improve methionine-choline-deficient diet-induced non-alcoholic steatohepatitis. And our previous study found that butyrate ameliorated endotoxemia in db/db mice. In this study, we aimed to explore the role of butyrate in the development of AFLD.MethodsC57BL/6 mice were treated with saline (normal control), alcohol with or without butyrate by gavage for 6 months. AFLD was evaluated by the levels of serum alcohol, aspartate aminotransferase (AST), alanine transaminase (ALT), triglyceride (TG) and intrahepatic TG. And the histology and inflammation in liver and colon were analyzed using hematoxylin-eosin (H&E) staining, immunohistochemistry and western blot. In addition, gut microbiota composition was analyzed using the V3-V4 regions of the bacterial 16S ribosomal RNA gene by sequence. Furthermore, we performed in vitro experiment to verify the role of butyrate in hepatocyte by western blot and transmission electron microscopy.ResultsWe found that butyrate ameliorated alcohol-induced hepatic steatosis and inflammation. Furthermore, chronic alcohol feeding induced dysbiosis and dysfunction of the gut microbiota, disrupted the intestinal barrier, and increased serum endotoxin levels. Meanwhile, butyrate improved the intestinal barrier disruption and endotoxemia induced by alcohol, but did not significantly alleviate the microbiome dysfunction. Mechanistically, butyrate ameliorated AFLD by inhibiting gasdermin D (GSDMD)-mediated pyroptosis.ConclusionsIn summary, we found butyrate ameliorated alcoholic fatty liver by down-regulating GSDMD-mediated pyroptosis. We speculate that butyrate improves AFLD mainly by maintaining intestinal barrier function and alleviating gut leakage. These findings suggest that butyrate may have the potential to serve as a novel treatment for AFLD.

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MicroRNA-141 ameliorates alcoholic hepatitis‑induced intestinal injury and intestinal endotoxemia partially via a TLR4-dependent mechanism.

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