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

• 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
• 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

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）。活的益生菌需要在肠道中定居