Butyrate ameliorates alcoholic fatty liver disease via reducing endotoxemia and inhibiting liver gasdermin D-mediated pyroptosis

Abstract

Background: Alcoholic 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 shortchain fatty acids produced by gut microbiota, has been shown to improve methionine-choline-deficient dietinduced 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.Methods: C57BL/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.Results: We 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.Conclusions: In 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.

Ampicillin exacerbates acetaminophen‐induced acute liver injury by inducing intestinal microbiota imbalance and butyrate reduction

“…Previous studies have shown that butyrate can improve several models of liver injury, including nonalcoholic fatty liver (NAFLD) 24,39–41 and alcoholic fatty liver (ALD) 42 . Mechanistically, these effects are attributed to the ability to promote barrier function.…”

“…Previous studies have shown that butyrate can improve several models of liver injury, including nonalcoholic fatty liver (NAFLD) 24,[39][40][41] and alcoholic fatty liver (ALD). 42 Mechanistically, these effects are attributed to the ability to promote barrier function. Our data suggest a novel mechanism by which butyrate alters susceptibility to ALI by activating the hepatic Nrf2 signalling pathway.…”

Sodium Butyrate Protects Against Ethanol-Induced Toxicity in SH-SY5Y Cell Line

“…As mentioned earlier, anti-inflammatory effects of BUT are well established (Cantu-Jungles et al 2019 ). Interestingly, BUT may also be of therapeutic potential in both alcoholic- and non-alcoholic fatty liver diseases (Ralli et al 2021 ; Zhang et al 2021 ). In addition, BUT has been advocated for treatment of obesity and sleep disorders (Baxter et al 2019 ; Szentirmai et al 2019 ) and most recently for control of cytokine storm associated with COVID-19 (Nithin et al 2021 ).…”

“…Indeed, it has been suggested that use of probiotic might be of potential use in prevention and treatment of alcohol-associated pathologies (Engen et al 2015 ; Lowe et al 2018 ; Rodriguez-Gonzalez and Orio 2020 ; Carbia et al 2021 ; Gupta et al 2021 ). In this regard, it was recently reported that butyrate (BUT) ameliorates alcoholic fatty liver disease in mice (Zhang et al 2021 ).…”

Seabuckthorn polysaccharide combined with astragalus polysaccharide ameliorate alcoholic fatty liver by regulating intestinal flora

“…At present, the treatment of AFLD mainly includes abstinence, nutritional support and drug therapy ( 6 ). The drug treatment mainly includes metadoxine, glucocorticoids, glycyrrhizic acid preparation and other drugs, which are not suitable for long-term use and are not specific drugs for AFLD ( 7 , 8 ). Therefore, the development of high-efficiency and low-toxicity therapeutic drugs for AFLD has become an urgent clinical need.…”