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 HIV 感染者 (PLWH) 的相关合并症，即使是那些接受有效抗逆转录病毒治疗的人 （艺术）。我们的初步数据支持一个模型，其中 AUD 和 HIV 联合损伤肠道，特别是 对微生物群的影响（消除产生抗炎短链脂肪酸 (SCFA) 的细菌） 和肠道屏障的完整性，加剧炎症。我们使用肠道类器官的初步数据也 提出了 HIV 期间 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能力较低，而酒精引起的肠道屏障破坏是由高水平的 氧化应激。最后，我们的初步数据还提出了一种增强信息完整性的潜在方法。 使用/不使用 AUD 的情况下，可增强肠道屏障并减少感染者的肠道源性炎症；促进 SCFA 的益生元。 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，可以减少人类肠道炎症。 总之，我们的数据支持我们的中心假设，即肠道对酒精介导的破坏的恢复能力 HIV 感染期间 SCFA 减少，导致微生物易位/炎症过度，并且 SCFA- 促进益生元可以增强艾滋病病毒感染者的肠道对酒精介导的破坏的恢复能力。 在目标 1 中，我们将检验以下假设：HIV+ 个体的肠道对酒精的抵抗力较低 - 介导的肠道屏障破坏比 HIV 阴性对照的肠道更严重。血液、尿液、粪便和肠道 将从四组中收集活检： (i) HIV-AUD-； (ii) HIV- AUD+，(iii) HIV+ ART+ AUD-； (iv) HIV+ 艺术+澳元+。首先，我们将比较：(a) 肠道屏障完整性，(b) 全身和肠道炎症、免疫 激活和氧化应激，(c) 微生物组和代谢组，以及 (d) HIV 储存库。其次，我们将 从 HIV 和 HIV+ ART+ 个体中生成回肠/结肠类器官，并检查他们的恢复能力 酒精引起的肠道屏障破坏。在目标 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，从而增强肠道的弹性 HIV+ 个体受到酒精介导的破坏。我们将提供 20 HIV+ ART+（10 AUD- 和 10 AUD+） 个人服用常用益生元低聚果糖 (FOS) 10 天。将收集粪便/血液 治疗前/治疗后。首先，我们将研究低聚果糖对微生物组、肠道相关代谢物、 和炎症。其次，我们将检查 FOS 前后微生物组/代谢组（过滤后的 来自粪便）对类器官对酒精介导的屏障破坏的恢复能力的影响。 本研究的结果可以为以下方面奠定基础：1）确定机制； 2）设计策略 预防 ART+ HIV 感染期间 AUD 相关合并症的发生。