Glycomic Modulation of Gut Microbiome During HIV Infection

项目概述：一个新兴的范式表明，肠道糖基化是维持肠道免疫的关键力量。 肠道与其微生物群之间的稳态关系。然而，目前还不清楚宿主糖基化是如何发生的。 这一机制有助于HIV相关的微生物易位和炎症。我们公布的数据显示， 在HIV阳性个体中，宿主循环糖组发生改变，尽管抗逆转录病毒治疗，这些变化仍持续存在 治疗（ART）。特别是，我们观察到持续的HIV相关的唾液酸损失（低唾液酸化）， 血浆糖蛋白这提示HIV感染也可能与糖组学改变有关 在其他身体隔间中，包括肠道。因此，我们使用了20例回肠和乙状结肠活检， HIV+ ART抑制的个体，发现肠道糖组学模式确实与不同的 微生物组成、炎症标志物和HIV持久性。特别是，我们发现：（1）增加 粘膜相关低唾液酸化O聚糖水平与肠道微生态失调和多样性降低相关 微生物组，更高的血浆炎症标志物水平，以及更高水平的回肠相关HIV DNA。 这些数据是有趣的，因为非艾滋病毒研究表明，唾液酸催化（去除，通过唾液酸酶） 驱动微生物生态失调/易位和肠道炎症。(2)岩藻糖基化聚糖水平升高 与更高的微生物组多样性，更低的生态失调和更低的炎症相关。这些相关性是 与报道一致，在一般人群中，肠道岩藻糖基化维持宿主-宿主共生， 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 持续性肠道糖组学改变-主要是低唾液酸化和缺乏适当的岩藻糖基化（岩藻糖基化障碍）- 这改变了微生物组的组成，导致微生物易位，炎症和艾滋病毒的持久性。 在目标1A中，我们将确定SIV感染对肠道糖组的影响，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18个纵向样本 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的表达增加，有助于SIV相关的微生物 易位在目标1B中，我们将确定ART治疗的HIV感染对肠道糖组的影响，使用 来自40名HIV+ ART抑制个体和匹配良好的HIV对照的横断面样本。在目标2 基于非HIV研究，证明唾液酸酶抑制剂或L-岩藻糖可减少微生物易位 和肠道炎症，我们将检验用唾液酸酶抑制剂或L-岩藻糖治疗将减少 使用SIV+ ART+猕猴的SIV介导的微生物易位和炎症。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，以减少艾滋病毒的持久性和/或预防/延迟艾滋病毒相关的并发症的发展。

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.