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

肠道微生物群对男男性行为艾滋病毒阳性男性肠道屏障功能和代谢综合征的影响

• 批准号: 10527542
• 负责人: Sean P Colgan
• 金额: $ 69.07万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10527542
• 关键词: Automobile Driving; Back; Bacteria; Bacterial Translocation; Biological Markers; Biopsy Specimen; Butyrates; Central obesity; Chronic; Chronic Kidney Failure; Couples; Defect; Development; Diet; Dyslipidemias; Enzymes; Epithelial; Event; Exhibits; Exposure to; Feces; Functional disorder; Gene Expression; Germ-Free; Gnotobiotic; HIV; HIV Seronegativity; HIV Seropositivity; Health; Human; Hypertension; Immune; In Vitro; Individual; Inflammation; Inflammatory; Insulin Resistance; Intestinal Mucosa; Intestines; Link; Measures; Metabolic; Metabolic Diseases; Metabolic Marker; Metabolic syndrome; Microbe; Mucins; Mucolytics; Mus; Obesity; Pathway Analysis; Persons; Phenotype; Plasma; Population; Process; Production; Role; Sialic Acids; System; Testing; Tight Junctions; Water; Work; bacterial community; cardiovascular risk factor; comorbidity; dysbiosis; gut bacteria; gut microbes; gut microbiome; improved; inflammatory marker; innovation; intestinal barrier; intestinal epithelium; lipopolysaccharide-binding protein; men who have sex with men; microbial; microbiome; microbiome composition; multiple omics; protein expression; systemic inflammatory response; transcriptomics; tributyrin

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.

项目概要/摘要 代谢综合征 (MS)，其特征是一系列病症，包括血脂异常、中腹部 肥胖、胰岛素抵抗和高血压在艾滋病毒感染者 (PLWH) 中普遍存在，并且使 他们发生心血管事件的风险更大。 MS 和相关的代谢紊乱已被强烈 与 HIV 之外的肠道微生物组活动相关，但尚未在 HIV 中进行深入研究 感染或未感染的男男性行为者 (MSM)，其肠道微生物组发生了高度改变 作品。肠道菌群失调、肠道屏障完整性受损和相关炎症 与某些人群中的多发性硬化症有关，但这是否是 HIV+ 患者多发性硬化症高水平的驱动因素 尽管细菌易位增加以及相关的全身性症状，MSM 尚未得到深入探索。 已知感染者会发生炎症。在我们正在进行的影响代谢疾病因素的研究中 在 HIV+ 和 HIV 阴性 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 将代谢健康状况不佳的相关微生物和免疫预测因子结合起来。我们的结果表明了核心作用 HIV+ MSM 中 MS 发展过程中与屏障功能障碍相关的炎症过程，但进一步 需要进行机制研究以充分了解屏障功能如何受到损害，包括潜在的 众所周知，肠道细菌和细菌衍生的代谢物会影响屏障。一键 我们正在进行的工作发现血浆 LBP 水平与丁酸生成量呈负相关 细菌;丁酸盐对肠上皮完整性具有明显的保护作用。我们也 观察到 LBP 与降解粘液糖蛋白上唾液酸的微生物之间呈正相关， 之前也发现这与 PLWH 的肠道屏障功能障碍和炎症过程有关。 因此，我们假设肠道菌群失调会影响 HIV+ MSM 的肠道屏障功能，并且这 通过包括 LPS 在内的微生物产物的易位促进 MS。为了检验这个假设，我们将 实现三个协调一致的具体目标。在目标 1 中，我们将确定肠道屏障功能障碍是否是 与没有 MS 的患者相比，患有 MS 的 HIV+ 和阴性 MSM 患者的比例更高，并且与丁酸缺乏有关 肠道微生物组中粘液溶解细菌的产生和/或活性。在目标 2 和 3 中，我们将验证 HIV/MS 相关肠道微生物与屏障功能障碍之间的关系 无菌小鼠，探索微生物产生丁酸盐和降解粘液的作用 这些过程中的糖蛋白。总而言之，这项工作将对 HIV 感染者肠道微生物群失调、屏障功能和 MS 之间的关系 也具有更广泛的影响，因为肠道屏障功能障碍与慢性 感染者的炎症和许多相关的合并症。