Glycomic Modulation of Gut Microbiome During HIV Infection

项目摘要：一个新出现的范例表明，肠道糖基化是维持 肠道与其微生物区系之间的动态平衡关系。然而，目前尚不清楚宿主如何糖基化。 机械导致艾滋病毒相关微生物移位和炎症。我们公布的数据显示， 在HIV患者中，宿主循环糖蛋白发生了变化，尽管有抗逆转录病毒治疗，这些变化仍然存在 治疗(ART)。特别是，我们观察到HIV相关的持续性唾液酸丢失(低唾液酸化)。 血浆糖蛋白。这向我们表明，艾滋病毒感染也可能与血糖变化有关。 在其他的身体隔间，包括内脏。因此，我们使用了20例回肠和乙状结肠活检。 抑制HIV抗逆转录病毒药物的个体发现，肠道血糖模式确实与不同的 微生物成分、炎症标志物和艾滋病毒持久性。特别是，我们发现：(1)增加了 粘膜相关、低唾液酸化的O-葡聚糖水平与肠道营养不良和多样性较少相关 微生物群，较高水平的血浆炎症标志物，以及较高水平的回肠相关艾滋病毒DNA。 这些数据很耐人寻味，因为非HIV研究表明唾液酸分解代谢(通过唾液酸酶去除) 导致微生物失调/移位和肠道炎症。(2)岩藻糖化多糖含量增加 与较高的微生物多样性、较低的生物失调和较低的炎症相关。这些相关性是 与报告一致，在普通人群中，肠道岩藻糖基化维持宿主-共生共生和 通过抑制细菌毒力基因来预防肠道炎症。我们假设艾滋病毒感染会导致 持续的肠道血糖改变--主要是唾液酸化过低和缺乏适当的岩藻糖化(Dys-岩藻糖化)- 这会改变微生物群的组成，导致微生物移位、炎症和艾滋病毒持续存在。 在目标1A中，我们将确定SIV感染对肠道糖类的影响以及这种影响对 微生物组组成和功能、炎症和病毒持久性，使用来自18个国家的纵向样本 猪尾猕猴。我们还将测试增强肠道唾液酸酶活性和/或 岩藻糖调节的细菌毒力基因表达增加，有助于SIV相关微生物 易位。在目标1B中，我们将确定经ART治疗的艾滋病毒感染对肠道糖蛋白的影响，使用 来自40名艾滋病毒抗逆转录病毒治疗受抑者和匹配良好的艾滋病毒对照组的横断面样本。在AIM 2 基于非艾滋病毒研究表明唾液酸酶抑制剂或L岩藻糖减少微生物易位 和肠道炎症，我们将检验唾液酸酶抑制剂或L岩藻糖治疗将减少的假设 SIV利用SIV ART猕猴介导的微生物移位和炎症。我们的工作旨在创造一个 新的范式，即宿主糖基化是在ART抑制期间塑造微生物组的关键力量 艾滋病毒感染。我们认为，利用这一机制将允许设计新的策略来操纵 这些力量有助于减少艾滋病毒的持久性和/或预防/延缓与艾滋病毒有关的共病的发展。

PROJECT SUMMARY: An emerging paradigm suggests that gut glycosylation is a key force in maintaining a homeostatic relationship between the gut and its microbiota. Nevertheless, it is unclear how host glycosylation machinery contributes to HIV-associated microbial translocation and inflammation. Our published data show that the host circulating glycome is altered in HIV+ individuals, and that these changes persist despite antiretroviral therapy (ART). In particular, we observe a persistent HIV-associated loss of sialic acid (hypo-sialylation) from plasma glycoproteins. This suggested to us that HIV infection may also be associated with glycomic alterations in other body compartments, including the gut. We therefore used ileum and sigmoid colon biopsies from 20 HIV+ ART-suppressed individuals and found that gut glycomic patterns are indeed associated with distinct microbial compositions, markers of inflammation, and HIV persistence. In particular, we found that: (1) Increased levels of mucosal-associated, hypo-sialylated O glycans correlated with a dysbiotic and less diverse gut microbiome, higher plasma levels of inflammatory markers, and higher levels of ileum-associated HIV DNA. These data are intriguing because non-HIV studies show that sialic acid catabolism (removal, via sialidase) drives microbial dysbiosis/translocation and intestinal inflammation. (2) Increased levels of fucosylated glycans correlated with higher microbiome diversity, lower dysbiosis, and lower inflammation. These correlations are consistent with reports, in the general population, that gut fucosylation sustains host-commensal symbiosis and prevents gut inflammation by suppressing bacterial virulence genes. We hypothesize that HIV infection causes persistent gut glycomic alterations – mainly hypo-sialylation and lack of proper fucosylation (dys-fucosylation) – that alter microbiome composition, leading to microbial translocation, inflammation, and HIV persistence. In Aim 1A, we will determine the impact of SIV infection on the gut glycome and the effects of this impact on microbiome composition and function, inflammation, and viral persistence, using longitudinal samples from 18 pig-tailed macaques. We will also test the mechanistic hypothesis that enhanced activity of gut sialidase, and/or increased expression of fucose-regulated bacterial virulence genes, contribute to SIV-associated microbial translocation. In Aim 1B, we will determine the impact of ART-treated HIV infection on the gut glycome, using cross-sectional samples from 40 HIV+ ART-suppressed individuals and well-matched HIV- controls. In Aim 2 and based on non-HIV studies demonstrating that sialidase inhibitor or L-fucose reduces microbial translocation and gut inflammation, we will test the hypothesis that treatment with sialidase inhibitor or L-fucose would reduce SIV-mediated microbial translocation and inflammation using SIV+ ART+ macaques. Our work aims to create a new paradigm, namely that host glycosylation is a key force that shapes the microbiome during ART-suppressed HIV infection. We propose that exploiting this mechanism will allow the design of novel strategies to manipulate these forces to reduce HIV persistence and/or prevent/delay the development of HIV-associated co-morbidities.