Severe alcoholic liver disease (ALD) has a high morbidity and mortality. Recent studies demonstrated that probiotics reversed alcohol-induced hepatic steatosis and inflammation, and improved liver enzymes in animal models and in patients. Our laboratory showed that administration of a probiotic strain, Lactobacillus rhamnosus Gorbach-Goldin (LGG), significantly improved liver enzymes and histology in alcohol treated mice. However, the beneficial mechanisms of action of LGG, either in viable bacteria form or in culture supernatant form, are not clear. Our overall hypothesis is that LGG increases intestinal cathelicidin-related antimicrobial peptide (CRAMP), intestinal trefoil factor (ITF) expression and intestinal short chain fatty acids (SCFAs), leading to improved gut microbiota homeostasis, intestinal barrier integrity and hepatic fat metabolism, and these are likely the mechanisms by which LGG supplementation attenuates alcohol induced liver injury. We evaluate mechanisms of LGG action with 4 specific aims:
Aim 1 will determine the role of CRAMP in the alcohol-mediated changes in gut microbiota and the role of CRAMP in the beneficial effects of LGG in experimental ALD. We will use CRAMP knockout mouse model of ALD to determine the role of CRAMP and LGG in alcohol-induced changes in gut microbiota using a metagenomic approach.
Aim 2 will determine the role of LGG in promoting ITF expression and evaluate whether ITF positively modulates intestinal tight junctions as a mechanism for improved intestinal barrier integrity in experimental ALD. We will use an ITF-secreting goblet cell line to evaluate the role of LGG in the production of ITF and the role of ITF in the modulation of intestinal tight junctions in an epithelial cell line. We will also examine th strategy that oral administration of recombinant human ITF attenuates alcohol-induced intestinal barrier and liver injury.
Aim 3 will determine the role and mechanisms of butyric acid in the beneficial effects of LGG on intestinal tight junctions in experimental ALD. A metabolomics approach will be used to analyze the changes in SCFAs induced by alcohol and LGG intervention in the intestinal lumen. We will explore the potential mechanisms underlying the role of butyric acid in the regulation of occludin expression involving intestinal histone deacetylases (HDACs), miR122a, and HIF-?-mediated signaling in vitro and in vivo.
Aim 4 will evaluate and compare the effectiveness of LGG supernatant (LGGs) with viable LGG (vLGG) and heat-inactivated LGG (hiLGG) in the prevention/therapy of ALD in mouse models. These three LGG preparations will be tested for the effectiveness in the prevention/therapy of ALD in three experimental models of ALD of steatosis, steatohepatitis and fibrosis. This study will have a major impact on the development of probiotic-based new therapeutic strategy for the prevention and treatment of ALD.
The goals of this project are to investigate the mechanisms of probiotic action on alcohol-induced liver injury. This study will have a major impact on the development of a probiotics-based new therapeutic strategy for the prevention and treatment of alcoholic liver disease.
|Shao, Tuo; Zhao, Cuiqing; Li, Fengyuan et al. (2018) Intestinal HIF-1? deletion exacerbates alcoholic liver disease by inducing intestinal dysbiosis and barrier dysfunction. J Hepatol 69:886-895|
|Yuan, Fuqiang; Chen, Xiaopan; Liu, Jie et al. (2018) Sulforaphane restores acetyl-histone H3 binding to Bcl-2 promoter and prevents apoptosis in ethanol-exposed neural crest cells and mouse embryos. Exp Neurol 300:60-66|
|Wu, Guicheng; Liu, Yanlong; Liu, Yunhuan et al. (2018) FGF 21 deficiency slows gastric emptying and reduces initial blood alcohol concentration in mice exposed to acute alcohol in fasting state. Biochem Biophys Res Commun 497:46-50|
|He, Liqing; Prodhan, Md Aminul Islam; Yuan, Fang et al. (2018) Simultaneous quantification of straight-chain and branched-chain short chain fatty acids by gas chromatography mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 1092:359-367|
|Kong, Xiaoxia; Yang, Ying; Ren, Li et al. (2017) Activation of autophagy attenuates EtOH-LPS-induced hepatic steatosis and injury through MD2 associated TLR4 signaling. Sci Rep 7:9292|
|Yuan, Fuqiang; Chen, Xiaopan; Liu, Jie et al. (2017) Up-regulation of Siah1 by ethanol triggers apoptosis in neural crest cells through p38 MAPK-mediated activation of p53 signaling pathway. Arch Toxicol 91:775-784|
|Liu, Liming; Zhao, Cuiqing; Yang, Ying et al. (2017) Fibroblast Growth Factor 21 Deficiency Attenuates Experimental Colitis-Induced Adipose Tissue Lipolysis. Gastroenterol Res Pract 2017:3089378|
|Li, Fengyuan; Duan, Kangmin; Wang, Cuiling et al. (2016) Probiotics and Alcoholic Liver Disease: Treatment and Potential Mechanisms. Gastroenterol Res Pract 2016:5491465|
|Cave, Matthew C; Clair, Heather B; Hardesty, Josiah E et al. (2016) Nuclear receptors and nonalcoholic fatty liver disease. Biochim Biophys Acta 1859:1083-1099|
|Liu, Yanlong; Zhao, Cuiqing; Xiao, Jian et al. (2016) Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury. Sci Rep 6:31026|
Showing the most recent 10 out of 13 publications