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: 10674923
• 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/10674923
• 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; Epithelium; 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; microbial products; 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.

项目摘要/摘要 代谢综合征（MS），其特征是一系列疾病，包括血脂异常，中心腹中心 肥胖，胰岛素抵抗和高血压在患有艾滋病毒（PLWH）的患者中普遍存在，并放置 他们面临心血管事件的更大风险。 MS和相关的代谢危险强烈 与HIV背景之外的肠道微生物组活性相关，但在HIV中尚未深入探讨 与男性发生性关系的感染或未感染的男性（MSM），他们的肠道微生物组发生了很大变化 作品。肠道营养不良，肠道屏障完整性受损和相关炎症已有 在某些人群中与MS有关，但是这是否是HIV+中MS高水平的驱动因素 即使细菌易位增加和相关的全身性，MSM尚未深入探索 已知炎症发生在PLWH中。在我们正在进行的影响代谢疾病的因素的研究中 在HIV+和HIV阴性MSM中，我们发现血浆脂多糖结合蛋白（LBP）升高为 代谢健康不良的最重要的预测指标，网络分析表明LBP形成了集线器 连接代谢健康不良的微生物和免疫预测因子。我们的结果表明核心角色 与HIV+ MSM中MS开发中与障碍功能障碍相关的炎症过程，但进一步 需要机械研究以充分了解屏障功能如何受到损害，包括潜力 肠道细菌和细菌衍生的代谢产物的作用，众所周知会影响屏障。一个钥匙 发现我们正在进行的工作是血浆LBP水平与产生丁酸酯的负相关性 细菌;丁酸酯对肠上皮完整性具有良好的保护性影响。我们也是 观察到LBP与微生物之间存在正相关，该微生物在粘液糖蛋白上降解唾液酸， 这也与PLWH之前的肠屏障功能障碍和炎症过程有关。 因此，我们假设肠道营养不良会影响HIV+ MSM中的肠道屏障功能，并且 通过包括LPS在内的微生物产品的转运来促进MS。为了检验这一假设，我们将 执行三个协调的特定目标。在AIM 1中，我们将确定肠屏障功能障碍是 与没有MS相比，MS的HIV+和负MSM较高，并且与丁酸酯缺乏有关 肠道微生物组中粘液溶液的产生和/或活性。在目标2和3中，我们将验证 艾滋病毒/MS相关的肠道微生物与使用肠道的障碍和障碍功能障碍之间的关系 gnotobiotic小鼠，探索丁酸酯和粘液降解的微生物产生的作用 这些过程中的糖蛋白。总之，这项工作将产生对 肠道微生物组营养不良，屏障功能和MS在受HIV感染的个体中的关系，将会 由于肠道屏障功能障碍与慢性有关，也具有更广泛的影响 PLWH中的炎症和许多相关的合并症。