Butyrate-Producing Probiotics Reduce Nonalcoholic Fatty Liver Disease Progression in Rats: New Insight into the Probiotics for the Gut-Liver Axis
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Open Access
- 16 May 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (5), e63388
- https://doi.org/10.1371/journal.pone.0063388
Abstract
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.Keywords
This publication has 64 references indexed in Scilit:
- PRAS40 Is an Insulin-Regulated Inhibitor of the mTORC1 Protein KinaseMolecular Cell, 2007
- Topical butyrate improves efficacy of 5‐ASA in refractory distal ulcerative colitis: results of a multicentre trialEuropean Journal of Clinical Investigation, 2003
- Prevention of antibiotic‐associated diarrhea in children by Clostridium butyricum MIYAIRIPediatrics International, 2003
- mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth MachineryCell, 2002
- Dynamic change of cells expressing MMP-2 mRNA and MT1-MMP mRNA in the recovery from liver fibrosis in the ratJournal of Hepatology, 2001
- Rationale for the luminal provision of butyrate in intestinal diseasesEuropean Journal of Nutrition, 2000
- Gene expression of interstitial collagenase in both progressive and recovery phase of rat liver fibrosis induced by carbon tetrachlorideJournal of Hepatology, 2000
- Preventive efficacy of butyrate enemas and oral administration of Clostridium butyricum M588 in dextran sodium sulfate-induced colitis in ratsThe Esophagus, 2000
- Transcription Factor Nrf2 Coordinately Regulates a Group of Oxidative Stress-inducible Genes in MacrophagesJournal of Biological Chemistry, 2000
- Transforming Growth Factor β1 Induces the Expression of α1(I) Procollagen Mrna by A Hydrogen Peroxide–C/Ebpβ–Dependent Mechanism in Rat Hepatic Stellate CellsHepatology, 1999