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- 艾滋病毒感染者（PLWH）的相关并发症，即使是那些接受有效抗逆转录病毒治疗的人 （ART）。我们的初步数据支持一个模型，在该模型中，AUD和HIV对肠道的联合损伤， 对微生物群的影响（消耗产生抗炎短链脂肪酸（SCFA）的细菌） 和肠道屏障完整性，加剧炎症。我们使用肠道类器官的初步数据也 这表明在HIV感染过程中AUD介导的肠道屏障功能变化的潜在机制：肠道 的HIV+个体对酒精引起的肠道屏障破坏的恢复力较低， 氧化应激最后，我们的初步数据还提出了一种潜在的方法，以提高完整的 肠屏障和减少肠源性炎症PLWH与/无AUD; SCFA促进益生元。 促进SCFA的益生元可预防酒精介导的对肠道屏障和炎症的不良影响 通过防止氧化应激。这些益生元是安全的，可以减少人类的肠道炎症。 总之，我们的数据支持了我们的核心假设，即肠道对酒精介导的破坏的恢复能力 在HIV感染期间减少，导致过度的微生物易位/炎症，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恢复力。 在目标1中，我们将检验HIV阳性个体的肠道对酒精的抵抗力较低的假设- 介导的肠道屏障破坏比来自HIV阴性对照的肠道。血液、尿液、粪便和肠道 将从四个组中收集活检：（i）HIV- AUD-;（ii）HIV- AUD+;（iii）HIV+ ART+ AUD-;和（iv）HIV+ ART+ AUD+。首先，我们将比较：（a）肠屏障完整性，（B）全身和肠道炎症，免疫 活化和氧化应激，（c）微生物组和代谢组，以及（d）HIV储库。二是 从HIV-和HIV+ ART+个体中产生回肠/结肠类器官，并检查它们对 酒精引起的肠屏障破坏。在目标2中，我们将检验促进SCFA的益生元 诱导可增强肠弹性的有益微生物的生长和/或活性 酒精介导的破坏。我们将提供20个HIV+ ART+（10 AUD-和10 AUD+） 使用常用的益生元低聚果糖（FOS）10天。将采集粪便/血液 治疗前/后。首先，我们将研究FOS对微生物组，肠道相关代谢物， 和炎症。其次，我们将研究FOS前后微生物组/代谢组的影响（过滤） 来自粪便）对类器官对酒精介导的屏障破坏的恢复力的影响。 本研究的结果可为以下工作奠定基础：1）识别机制; 2）设计策略 预防ART+ HIV感染期间发生AUD相关合并症。