Gut Microbiota-Mediated Inflammatory Interactions Between Alcohol Use Disorders and HIV Infection

肠道微生物介导的酒精使用障碍和 HIV 感染之间的炎症相互作用

• 批准号: 10838766
• 负责人: Mohamed Abdel Mohsen
• 金额: $ 73.93万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10838766
• 关键词: Adverse effects; Aftercare; Alcohols; Anti-Inflammatory Agents; Bacteria; Biopsy; Blood; Colon; DNA; Data; Development; Disease; Disease Progression; Exhibits; Feces; Filtration; Foundations; Growth; HIV; HIV Infections; HIV Seronegativity; HIV antiretroviral; Heavy Drinking; High Prevalence; Human; Individual; Inflammation; Inflammatory; Intestines; Leaky Gut; Link; Liver diseases; Mediating; Modeling; Morbidity - disease rate; Mus; Organ; Organoids; Oxidative Stress; Patients; Permeability; Persons; Plasma; Prevalence; Proteins; Publishing; RNA; Reporting; Severities; Sex Orientation; Sigmoid colon; Testing; Tight Junctions; Tissues; United States; Urine; Viral; Volatile Fatty Acids; alcohol misuse; alcohol prevention; alcohol use disorder; antiretroviral therapy; beneficial microorganism; body system; comorbidity; decrease resilience; design; dysbiosis; fructooligosaccharide; gut inflammation; gut microbiome; gut microbiota; immune activation; improved; intestinal barrier; metabolome; microbial; microbiome; microbiome composition; microbiota; mortality; novel strategies; prebiotics; prevent; promote resilience; reduced alcohol use; resilience; systemic inflammatory response; zonulin

PROJECT SUMMARY. Alcohol use disorder (AUD) has been associated with a high prevalence of inflammation- associated co-morbidities in people living with HIV (PLWH), even those receiving effective antiretroviral therapy (ART). Our preliminary data support a model in which the combined insult of AUD and HIV on the gut, specifically on the microbiota (depletion of the bacteria that produce the anti-inflammatory short-chain fatty acids (SCFAs)) and intestinal barrier integrity, exacerbates inflammation. Our preliminary data using intestinal organoids also suggest a potential mechanism for AUD-mediated changes in the gut barrier function during HIV: the intestines of HIV+ individuals have low resilience to alcohol-induced intestinal barrier disruption caused by high levels of oxidative stress. Finally, our preliminary data also suggest a potential approach to enhance the integrity of the intestinal barrier and reduce gut derived inflammation in PLWH with/without AUD; SCFA-promoting prebiotics. SCFA-promoting prebiotics prevent alcohol-mediated adverse effects on the intestinal barrier and inflammation by preventing oxidative stress. These prebiotics are safe and decrease gut inflammation in humans. Together, our data support our central hypothesis that the intestinal resilience to alcohol-mediated disruption is reduced during HIV infection leading to exaggerated microbial translocation/inflammation, and that SCFA- promoting prebiotics can enhance the resilience of the gut from HIV+ individuals to alcohol-mediated disruption. In Aim 1, we will test the hypothesis that intestines from HIV+ individuals have lower resilience to alcohol- mediated gut barrier disruption than intestines from HIV-negative controls. Blood, urine, stool, and intestinal biopsies will be collected from four groups: (i) HIV- AUD-; (ii) HIV- AUD+, (iii) HIV+ ART+ AUD-; and (iv) HIV+ ART+ AUD+. First, we will compare: (a) intestinal barrier integrity, (b) systemic and gut inflammation, immune activation, and oxidative stress, (c) microbiome and metabolome, and (d) HIV reservoirs. Second, we will generate Ileal/colonic organoids from the HIV- and HIV+ ART+ individuals and examine their resilience to alcohol-induced intestinal barrier disruption. In Aim 2, we will test the hypothesis that SCFA-promoting prebiotics induce the growth and/or activity of beneficial microorganisms that can enhance the resilience of the intestines of HIV+ individuals to alcohol-mediated disruption. We will provide 20 HIV+ ART+ (10 AUD- and 10 AUD+) individuals with commonly used prebiotics fructooligosaccharides (FOS) for 10 days. Stool/blood will be collected before/after the treatment. First, we will examine the impact of FOS on the microbiome, gut-related metabolites, and inflammation. Second, we will examine the impact of pre- and post-FOS microbiome/metabolome (filtered from stool) on the resilience of organoids to alcohol-mediated barrier disruption. The results of this study can build a foundation for: 1) identifying the mechanisms; and 2) designing strategies to prevent the development, of AUD-associated co-morbidities during ART+ HIV infection.

项目摘要。酒精使用障碍（AUD）与炎症的高患病率有关 艾滋病毒（PLWH）患者的相关合并症，甚至那些接受有效抗逆转录病毒疗法的人 （艺术）。我们的初步数据支持一个模型，其中肠道上的AUD和HIV的组合侮辱，特别是 在微生物群上（产生抗炎短链脂肪酸（SCFAS）的细菌的耗竭） 和肠屏障完整性，加剧了炎症。我们的初步数据也是使用肠道器官 提出了艾滋病毒期间肠道屏障功能变化的潜在机制：肠 艾滋病毒+个体对酒精引起的肠道屏障破坏的韧性较低 氧化应激。最后，我们的初步数据还提出了一种潜在的方法来增强完整性 肠壁屏障并减少肠道引起的肠道炎症，随着/不带有AUD；促进SCFA的益生元。 促进SCFA的益生元可以防止酒精介导的肠屏障和炎症的不良影响 通过预防氧化应激。这些益生元是安全的，可减少人类的肠道炎症。 一起，我们的数据支持我们的核心假设，即酒精介导的肠道韧性 在HIV感染期间降低导致微生物易位/炎症，并降低SCFA- 促进益生元可以增强肠道从HIV+个体到酒精介导的破坏的弹性。 在AIM 1中，我们将检验以下假设：HIV+个体的肠道对酒精的韧性较低 - 介导的肠道屏障破坏比来自HIV阴性控制的肠道破坏。血液，尿液，凳子和肠道 活检将从四组中收集：（i）HIV- aud-; （ii）HIV- aud+，（iii）HIV+ Art+ Aud-; （iv）HIV+ ART+ AUD+。首先，我们将比较：（a）肠道屏障完整性，（b）系统性和肠炎，免疫 激活和氧化应激，（c）微生物组和代谢组，以及（d）HIV储层。第二，我们会的 从HIV和HIV+ ART+个体产生回肠/结肠类器官，并检查其对 酒精引起的肠道屏障破坏。在AIM 2中，我们将检验以下假设：促进SCFA的益生元 诱导有益微生物的生长和/或活性，可以增强肠的弹性 艾滋病毒+个体对酒精介导的破坏。我们将提供20个HIV+ ART+（10 AUD和10 AUD+） 患有常用的益生元果糖（FOS）的个体10天。将收集粪便/血液 治疗前/之后。首先，我们将研究FOS对微生物组，肠道相关的代谢产物的影响， 和炎症。其次，我们将研究前和后微生物组/代谢组的影响（过滤 从凳子上）关于器官的弹性到酒精介导的屏障破坏。 这项研究的结果可以为：1）确定机制； 2）设计策略 为了防止在ART+ HIV感染期间与AUD相关的合并症的发展。