Mechanisms of Probiotics in Alcoholic Liver Disease

益生菌治疗酒精性肝病的机制

• 批准号: 10794806
• 负责人: WENKE FENG
• 金额: $ 42.7万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10794806
• 关键词: Acute; Agonist; Alcohol-Induced Disorders; Alcoholic Liver Diseases; Aryl Hydrocarbon Receptor; Bacteria; Bacterial Translocation; Bilophila wadsworthia; Cells; Chronic; Development; Digestive System Disorders; Disease; Endocytosis; Environment; Epithelial Cells; Epithelium; Experimental Models; Ginger; Goals; Growth; Homeostasis; Intestines; Lactobacillus casei rhamnosus; Mediating; Mus; Natural regeneration; Oxidative Stress Induction; Pathogenicity; Pathway interactions; Play; Prevention; Prevention strategy; Probiotics; Production; Receptor Signaling; Regenerating islet derived protein 3-Gamma; Role; Signal Transduction; Testing; Therapeutic Effect; Tight Junctions; Tryptophan; Up-Regulation; alcohol abuse therapy; alcohol exposure; aryl hydrocarbon receptor ligand; dysbiosis; exosome; gut colonization; gut inflammation; gut microbiota; improved; interleukin-22; intestinal barrier; intestinal epithelium; islet; metabolomics; microbial; mouse model; nanoparticle; novel therapeutic intervention; pathogenic bacteria; prebiotics; prevent; probiotic therapy; protective effect; transcytosis

Probiotics have been used to prevent/treat a variety of digestive diseases including alcoholic liver disease (ALD). Live probiotics need to colonize the gut to exert their function. Unfortunately, underlying disease states provide an unfavorable environment for probiotic bacterial gut colonization, which diminishes probiotics’ function. In last few years, we showed that LGG culture supernatant (LGGs, without live bacteria) was effective in the prevention of ALD in experimental models of acute and chronic alcohol exposure in mice. However, how LGG supernatant exerts its therapeutic effects is not fully understood. Exosomes are nanoparticles (NPs) derived from cell endocytosis which act as transmitters between cells. Recent studies show that bacteria, both Gram-negative and Gram-positive, produce NPs. The NPs derived from “bad” bacteria have been demonstrated to be pathogenic. However, “good” bacteria-, probiotics-derived NPs have not been studied. Our preliminary study showed that administration of LGG-derived exosome-like NPs (LDNPs) effectively reversed ALD in binge-on- chronic alcohol exposure mouse model, suggesting that probiotic LGGs may exert its function through LDNPs in ALD. LDNPs administration markedly increased intestinal AhR activity, IL-22, regenerating islet-derived 3 (Reg3) beta and gamma expression, which play a key role in maintaining gut microbiota homeostasis and preventing bacterial intestinal transcytosis. In addition, LDNPs administration significantly increased intestinal epithelial cell (IEC) tight junctions and decreased circulating LPS concentration, associated with upregulation of intestinal Nrf2 signaling, which is known for protecting intestinal barrier junctions against oxidative stress-induced damage by alcohol. Metabolomic analysis revealed that LDNPs contain high levels of microbial metabolites of tryptophan, which are AhR ligands, indicating LDNPs may activate intestinal AhR signaling. Furthermore, we demonstrated that ginger exosome-like nanoparticles (GDNPs) are preferentially taken up by LGG, suggesting that GDNP may serve as a prebiotic to enhance the effects of LGG. These preliminary studies provide the groundwork for our central hypothesis that, by activating intestinal AhR-Nrf2 signaling, LDNPs increase intestinal expression of Il-22, Reg3 and tight junctions, and modulate gut microbiota homeostasis and enhance intestinal barrier function, leading to the suppression of ALD. We will test our hypothesis in following three specific aims: (1) Determine the role of bacteria-derived NPs in ALD; (2) Define the mechanisms of the beneficial effect of LDNPs in ALD; (3) Determine whether ginger-derived exosome-like nanoparticles (GDNPs) treatment enhances LDNP production and AhR agonist enrichment that lead to improved effects of LDNPs against ALD. Completion of this study is expected to significantly impact the development of LGG-based probiotic therapeutics in the treatment of alcohol-associated liver diseases.

益生菌已被用于预防/治疗多种消化系统疾病，包括酒精性肝病（ALD）。

项目成果

MicroRNA-135a Protects Against Ethanol-Induced Apoptosis in Neural Crest Cells and Craniofacial Defects in Zebrafish by Modulating the Siah1/p38/p53 Pathway.

• DOI: 10.3389/fcell.2020.583959
• 发表时间: 2020
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Yuan F;Yun Y;Fan H;Li Y;Lu L;Liu J;Feng W;Chen SY
• 通讯作者: Chen SY

Deficiency of Cathelicidin Attenuates High-Fat Diet Plus Alcohol-Induced Liver Injury through FGF21/Adiponectin Regulation.

• DOI: 10.3390/cells10123333
• 发表时间: 2021-11-27
• 期刊: Cells
• 影响因子: 6
• 作者: Li F;Chen J;Liu Y;Gu Z;Jiang M;Zhang L;Chen SY;Deng Z;McClain CJ;Feng W
• 通讯作者: Feng W

Activation of autophagy attenuates EtOH-LPS-induced hepatic steatosis and injury through MD2 associated TLR4 signaling.

自噬的激活通过 MD2 相关的 TLR4 信号减弱 EtOH-LPS 诱导的肝脂肪变性和损伤

• DOI: 10.1038/s41598-017-09045-z
• 发表时间: 2017-08-24
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Kong X;Yang Y;Ren L;Shao T;Li F;Zhao C;Liu L;Zhang H;McClain CJ;Feng W
• 通讯作者: Feng W

Up-regulation of Siah1 by ethanol triggers apoptosis in neural crest cells through p38 MAPK-mediated activation of p53 signaling pathway.

• DOI: 10.1007/s00204-016-1746-3
• 发表时间: 2017-02
• 期刊: Archives of toxicology
• 影响因子: 6.1
• 作者: Yuan F;Chen X;Liu J;Feng W;Wu X;Chen SY
• 通讯作者: Chen SY

Up-regulation of microRNA-34a mediates ethanol-induced impairment of neural crest cell migration in vitro and in zebrafish embryos through modulating epithelial-mesenchymal transition by targeting Snail1.

• DOI: 10.1016/j.toxlet.2022.01.004
• 发表时间: 2022-04-01
• 期刊: TOXICOLOGY LETTERS
• 影响因子: 3.5
• 作者: Fan, Huadong;Li, Yihong;Yuan, Fuqiang;Lu, Lanhai;Liu, Jie;Feng, Wenke;Zhang, Huang-Ge;Chen, Shao-yu
• 通讯作者: Chen, Shao-yu