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.

项目总结/摘要 代谢综合征（MS），以一系列疾病为特征，包括血脂异常、中央腹部 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， 他们患心血管疾病的风险更大。MS和相关的代谢紊乱已经被强烈地 与HIV背景外的肠道微生物组活动相关，但尚未在HIV中深入研究 感染或未感染的男性与男性发生性关系（MSM），肠道微生物组高度改变 混合物.肠道生态失调、受损的肠道屏障完整性和相关的炎症已经导致了 在某些人群中与MS有关，但这是否是HIV+患者高水平MS的驱动因素 MSM尚未深入研究，即使增加细菌易位和相关的系统性 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阳性和HIV阴性的MSM中，我们发现血浆脂多糖结合蛋白（LBP）升高是 代谢健康状况不佳的最重要的预测因素，网络分析显示LBP形成了一个枢纽， 加入了代谢健康不良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，炎症过程与屏障功能障碍有关，但进一步 需要进行机制研究，以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。一个关键 我们正在进行的研究发现，血浆LBP水平与丁酸产生呈负相关。 丁酸盐对肠上皮完整性具有良好的保护作用。我们也 观察到LBP和降解粘液糖蛋白上唾液酸的微生物之间的正相关性， 这也与PLWH中肠屏障功能障碍和炎症过程有关。 因此，我们假设肠道生态失调影响HIV+ MSM的肠道屏障功能， 通过包括LPS在内的微生物产物的易位促进MS。为了验证这个假设，我们将 实现三个协调一致的具体目标。在目标1中，我们将确定肠屏障功能障碍是否是 与无MS相比，HIV+和阴性MSM伴MS的患者更高，且与丁酸盐缺乏相关- 消化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，我们将核实 HIV/MS相关肠道微生物和屏障功能障碍之间的关系， gnotobiotic小鼠，并探讨微生物的作用下产生丁酸和降解粘液 糖蛋白在这些过程中。总之，这项工作将产生一个机械的理解， HIV感染者肠道微生物群失调、屏障功能和MS之间的关系 具有更广泛的影响，因为肠道屏障功能障碍与慢性 炎症和PLWH中的许多相关共病。