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.

益生菌已用于预防/治疗各种消化系统疾病，包括酒精性肝病（ALD）。 实时益生菌需要定居肠道以发挥其功能。不幸的是，潜在的疾病国家提供 益生菌肠道定植的不利环境，可降低益生菌的功能。最后 几年，我们表明LGG培养上清液（LGG，无活细菌）有效预防 小鼠急性和慢性酒精暴露的实验模型中ALD的ALD。但是，如何上清液 发挥其治疗作用尚未完全理解。外泌体是源自细胞的纳米颗粒（NP） 内吞作用，充当细胞之间的发射机。最近的研究表明，细菌，均为革兰氏阴性 和革兰氏阳性，产生NP。已证明源自“坏”细菌的NP是 致病性。但是，尚未研究“好”细菌，益生菌衍生的NP。我们的初步研究 表明，在暴饮暴食中，施用LGG衍生的外泌体样NP（LDNP）有效地逆转了ALD 慢性酒精暴露小鼠模型，表明益生菌LGG可以通过LDNP执行其功能 在Ald。 LDNPS施用显着增加了肠AHR活性，IL-22，再生胰岛衍生3 （reg3）beta和伽马表达，它们在维持肠道菌群稳态和 防止细菌肠道胞肿。另外，LDNPS给药显着增加了肠道 上皮细胞（IEC）紧密连接和改善的循环LPS浓度，与上调有关 肠NRF2信号传导，该信号传导以保护肠道屏障连接抗氧化应激诱导而闻名 酒精损害。代谢组学分析表明，LDNP含有高水平的微生物代谢产物 色氨酸是AHR配体，表明LDNP可能会激活肠道AHR信号。此外，我们 证明姜外泌体样纳米颗粒（GDNP）最好被LGG吸收，表明 该GDNP可以作为益生元来增强LGG的作用。这些初步研究提供了 我们的中心假设的基础，即通过激活肠道AHR-NRF2信号，LDNP会增加肠道 IL-22，Reg3和紧密连接的表达，并调节肠道菌群稳态并增强肠 屏障功能，导致ALD抑制。我们将在以下三个具体目标中检验我们的假设： （1）确定细菌衍生的NP在ALD中的作用； （2）定义有益作用的机制 ALD中的LDNP； （3）确定生姜衍生的外泌体样纳米颗粒（GDNP）是否增强 LDNP的产生和AHR激动剂富集可改善LDNP对ALD的影响。完成 预计这项研究将显着影响基于LGG的益生菌治疗的发展 治疗酒精相关的肝病。

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

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

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

Fibroblast Growth Factor 21 Deficiency Attenuates Experimental Colitis-Induced Adipose Tissue Lipolysis.

成纤维细胞生长因子 21 缺乏会减弱实验性结肠炎诱导的脂肪组织脂解作用

• DOI: 10.1155/2017/3089378
• 发表时间: 2017
• 期刊: Gastroenterology research and practice
• 影响因子: 2
• 作者: Liu L;Zhao C;Yang Y;Kong X;Shao T;Ren L;Zhuang X;Yin B;Dryden G;McClain C;Luan W;Feng W
• 通讯作者: Feng W