Gut microbiome effects on intestinal barrier function and metabolic syndrome in HIV positive men who have sex with men

项目摘要/摘要 代谢综合征(MS)，以一系列疾病为特征，包括血脂异常、中腹 肥胖、胰岛素抵抗和高血压在艾滋病毒携带者(PLWH)中很普遍，并将 他们发生心血管事件的风险更大。多发性硬化症和相关的代谢紊乱一直很强烈 与肠道微生物群活动的相关性超出了HIV的范围，但尚未在HIV中深入研究 感染或未感染的男男性行为者(MSM)，他们的肠道微生物群发生了很大的变化 组成。肠道生物失调、肠道屏障完整性受损及相关炎症 在某些人群中与多发性硬化症有关，但这是否是艾滋病毒中多发性硬化症水平高的驱动因素 MSM尚未得到深入研究，尽管细菌易位增加并与系统性疾病相关 已知炎症发生在PLWH中。在我们正在进行的影响代谢性疾病的因素的研究中 在HIV和HIV阴性的MSM中，我们发现血浆脂多糖结合蛋白(LBP)升高 代谢健康状况不佳的最重要预测因素，网络分析显示，LBP形成了一个枢纽 加入代谢健康状况不佳的相关微生物和免疫预测因子。我们的研究结果表明， 在HIV MSM的MS发展中与屏障功能障碍有关的炎症过程，但进一步 需要机制研究来充分了解屏障功能是如何受损的，包括潜在的 肠道细菌和细菌衍生的代谢物的作用，这是众所周知的影响屏障。一键 我们正在进行的研究发现，血浆LBP水平与丁酸盐产量之间存在负相关 细菌；丁酸盐对肠道上皮完整性有很好的保护作用。我们也 观察到LBP与一种降解粘液糖蛋白上唾液酸的微生物呈正相关， 它也与PLWH的肠道屏障功能障碍和炎症过程有关。 因此，我们假设肠道生物失调影响HIV男男性接触者的肠道屏障功能，并且这 通过包括脂多糖在内的微生物产物的移位促进多发性硬化。为了检验这一假设，我们将 执行三个协调一致的具体目标。在目标1中，我们将确定肠屏障功能障碍是否 合并多发性硬化症的HIV和阴性MSM的患病率高于无多发性硬化症的患者，并与丁酸缺乏有关。 肠道微生物群中黏液溶解细菌的产生和/或活性。在目标2和目标3中，我们将验证 肠道HIV/MS相关微生物与肠系膜屏障功能障碍的关系 并探讨微生物对丁酸的产生和粘液降解的作用 这些过程中的糖蛋白。综上所述，这项工作将产生对 HIV感染者肠道微生物群失调、屏障功能和多发性硬化与意志的关系 也有更广泛的影响，因为肠屏障功能障碍与慢性 炎症，以及与PLWH相关的许多并存。

Project Summary/Abstract Metabolic syndrome (MS), characterized by a cluster of conditions including dyslipidemia, central abdominal obesity, insulin resistance, and high blood pressure, is prevalent in people living with HIV (PLWH), and puts them at greater risk of cardiovascular events. MS and related metabolic derangements have been strongly correlated with gut microbiome activity outside the context of HIV but has not been deeply explored in HIV infected or uninfected men who have sex with men (MSM), who have a highly altered gut microbiome composition. Intestinal dysbiosis, compromised intestinal barrier integrity and associated inflammation has been linked with MS in certain populations, but whether this is a driving factor of high levels of MS in HIV+ MSM has not been deeply explored, even though increased bacterial translocation and associated systemic inflammation is known to occur in PLWH. In our ongoing studies of factors that influence metabolic disease across HIV+ and HIV negative MSM, we found elevated plasma lipopolysaccharide binding protein (LBP) to be the most important predictor of poor metabolic health, with network analysis showing that LBP formed a hub joining correlated microbial and immune predictors of poor metabolic health. Our results suggest a central role of inflammatory processes linked with barrier dysfunction in the development of MS in HIV+ MSM, but further mechanistic studies are needed to fully understand how barrier function is compromised, including a potential role for gut bacteria and bacterial-derived metabolites, which are well known to influence barrier. One key finding of our ongoing work was a negative correlation between plasma LBP levels and butyrate-producing bacteria; Butyrate has a well-characterized protective influence on intestinal epithelial integrity. We also observed a positive correlation between LBP and a microbe that degrades sialic acids on mucus glycoproteins, which has also been linked with intestinal barrier dysfunction and inflammatory processes in PLWH previously. Thus, we hypothesize that intestinal dysbiosis impacts gut barrier function in HIV+ MSM, and that this promotes MS via the translocation of microbial products including LPS. To test this hypothesis, we will perform three coordinated specific aims. In Aim 1 we will determine whether intestinal barrier dysfunction is higher in HIV+ and negative MSM with MS compared to without MS and related to deficiency in butyrate- production and/or activity of mucolytic bacteria in the gut microbiome. In Aims 2 and 3 we will verify the relationship between HIV/MS-associated gut microbes and barrier dysfunction using enteroides and gnotobiotic mice, and explore the role of microbial production of butyrate and degradation of mucus glycoproteins in these processes. Taken together this work will produce a mechanistic understanding of the relationship between gut microbiome dysbiosis, barrier function, and MS in HIV-infected individuals and will have broader implications as well, since intestinal barrier dysfunction has been linked with chronic inflammation, and many associated co-morbidities in PLWH.