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

项目总结。酒精使用障碍(AUD)与炎症的高患病率有关- 艾滋病毒携带者(PLWH)的相关并存，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这样一个模型，在这个模型中，澳州大学和艾滋病毒对肠道的联合侮辱，特别是 微生物区系(产生抗炎短链脂肪酸(SCFA)的细菌的枯竭) 和肠道屏障的完整性，加剧炎症。我们使用肠道有机化合物的初步数据也 提示艾滋病期间AUD介导的肠道屏障功能改变的一个潜在机制：肠道 的人对酒精引起的肠道屏障破坏的抵抗力较低，这是由高水平的 氧化应激。最后，我们的初步数据也提出了一种潜在的方法来增强 在使用/不使用AUD的PLWH中，肠道屏障和减少肠源性炎症；促进SCFA的益生元。 促进单链脂肪酸的益生元预防酒精对肠道屏障和炎症的不利影响 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中心假设，即肠道对酒精介导的破坏的弹性 在艾滋病毒感染期间减少，从而导致微生物移位/炎症的夸大，并且SCFA- 推广益生元可以增强HIV+个体肠道对酒精介导的破坏的弹性。 在目标1中，我们将检验这样一个假设，即HIV+患者的肠道对酒精的抵抗力较低- 与HIV阴性对照的肠道相比，介导的肠道屏障破坏。血、尿、大便和肠道 活检将从四个组收集：(一)艾滋病毒-AUD-；(二)艾滋病毒-AUD+；(三)艾滋病毒+抗逆转录病毒+AUD-；和(四)艾滋病毒+ 艺术+澳元+。首先，我们将比较：(A)肠道屏障的完整性，(B)全身和肠道炎症，免疫 (C)微生物组和代谢组，以及(D)艾滋病毒宿主。第二，我们将 从HIV携带者和HIV+ART+个体产生回肠/结肠类器官，并检测它们对 酒精引起的肠道屏障破坏。在目标2中，我们将检验SCFA促进益生元的假设 诱导有益微生物的生长和/或活动，以增强肠道的弹性 艾滋病病毒携带者对酒精介导的破坏的反应。我们将提供20个HIV+ART+(10个澳元和10个澳元+) 服用常用益生素低聚果糖(FOS)10天的个体。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群、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)的影响 从粪便)对有机物对酒精介导的屏障破坏的弹性的影响。 这项研究的结果可以为：1)确定机制；2)设计策略奠定基础 为了防止在ART+HIV感染期间发生与AUD相关的并存疾病。

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.