Probiotic-derived nano-particles in alcoholic liver disease

益生菌衍生的纳米颗粒治疗酒精性肝病

基本信息

批准号：
10056416
负责人：
WENKE FENG
金额：
$ 8.07万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10056416
关键词：
Acute Agonist Alcohol-Induced Disorders Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Aryl Hydrocarbon Receptor Bacteria Bacterial Translocation Bilophila wadsworthia Biological Markers Cells Chronic Clinical Development Digestive System Disorders Disease Endocytosis Environment Epithelial Epithelial Cells Evaluation Experimental Models Functional disorder Future Ginger Growth Homeostasis Intestines Lead Liver diseases Mediating Mus National Institute on Alcohol Abuse and Alcoholism Natural regeneration Outcome Oxidative Stress Pathogenicity Pathway interactions Patients Play Prevention Prevention therapy Probiotics Production Receptor Signaling Role Sampling Signal Transduction Testing Therapeutic Effect Tight Junctions Tryptophan Up-Regulation alcohol abuse therapy alcohol exposure aryl hydrocarbon receptor ligand base clinical application disorder prevention dysbiosis exosome gut colonization gut microbes gut microbiota improved inflammatory disease of the intestine interleukin-22 intestinal barrier intestinal epithelium islet metabolomics microbial mouse model nanoparticle nutrition organ injury pathogenic bacteria prebiotics prevent probiotic therapy programs protective effect transcytosis

项目摘要

Probiotics have been used to prevent/treat 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 the 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 the binge-on-chronic alcohol exposure mouse model, suggesting that probiotic LGGs may exert its function through LDNPs in ALD. Administration of LDNPs markedly increased intestinal AhR activity, IL-22, and regenerating islet-derived 3 (Reg3) β and γ 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 four specific aims: (1) Determine the role of bacteria- derived NPs in ALD; (2) Define the mechanisms of the beneficial effects of LDNPs in ALD; (3) Determine whether GDNPs treatment enhances LDNP production and AhR agonist enrichment that lead to improved effects of LDNPs against ALD; and (4) Evaluate the intestinal AhR-Nrf2 signaling in alcoholic hepatitis patients treated with LGG. 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/治疗酒精性肝病（ALD）。活益生菌需要在肠道中定殖。不幸的是，潜在的疾病状态为益生菌提供了不利的环境。细菌肠道定植，会削弱益生菌的功能在过去的几年里，我们发现 LGG。培养上清液（LGG，不含活细菌）在实验模型中可有效预防 ALD 然而，LGG 上清液如何发挥其治疗作用尚不清楚。外泌体是源自细胞内吞作用的纳米颗粒（NP），充当递质。最近的研究表明，革兰氏阴性和革兰氏阳性细菌都会产生纳米颗粒。源自“坏”细菌的纳米颗粒已被证明具有致病性，然而，“好”细菌却具有致病性。我们的初步研究表明，益生菌衍生的 NP 的施用来自 LGG。外泌体样 NP（LDNP）可有效逆转慢性酒精暴露小鼠模型中的 ALD，表明益生菌 LGGs 可能通过 LDNPs 在 LDNPs 给药中显着发挥其功能。增加肠道 AhR 活性、IL-22 和再生胰岛衍生 3 (Reg3) β 和 γ 表达，这些作用此外，在维持肠道微生物群稳态和防止细菌肠道转胞吞作用方面发挥着关键作用。 LDNPs 给药显着增加肠上皮细胞 (IEC) 紧密连接并减少循环 LPS 浓度与肠道 Nrf2 信号传导的上调相关，众所周知保护肠道屏障连接免受酒精代谢应激引起的损伤。揭示 LDNP 含有高水平的色氨酸微生物代谢物，它们是 AhR 配体，表明 LDNPs 可能激活肠道 AhR 信号传导此外，我们证明了姜外泌体样。纳米粒子 (GDNP) 优先被 LGG 吸收，表明 GDNP 可以作为益生元这些初步研究为我们的中心假设奠定了基础：通过激活肠道 AhR-Nrf2 信号传导，LDNP 增加肠道 IL-22、Reg3 和紧密表达连接，调节肠道微生物群稳态并增强肠道屏障功能，从而导致我们将通过以下四个具体目标来检验我们的假设：（1）确定细菌的作用- (2) 定义 LDNP 在 ALD 中的有益作用机制； (3) 确定是否 GDNPs 处理可增强 LDNP 的产生和 AhR 激动剂的富集，从而改善 LDNP 对抗 ALD；以及 (4) 评估酒精性肝炎患者的肠道 AhR-Nrf2 信号传导 LGG 预计这项研究的完成将对基于 LGG 的益生菌的开发产生重大影响。治疗与酒精相关的肝病。