Fecal microbial transplantation to reduce HIV-associated inflammation

粪便微生物移植可减少艾滋病毒相关炎症

• 批准号: 8992256
• 负责人: Ma Somsouk
• 金额: $ 23.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8992256
• 关键词: Acquired Immunodeficiency Syndrome; Address; Biological Assay; Biological Markers; Biology; Biopsy; CD4 Lymphocyte Count; CD4/CD8 ratio procedure; CD8B1 gene; Cardiovascular Diseases; Cardiovascular system; Cells; Characteristics; Chronic; Clinical; Clinical Investigator; Clinical Trials; Clostridium difficile; Colonoscopy; Communities; Disease Progression; Engraftment; Epithelial; Event; Exhibits; Feces; Flow Cytometry; Gastroenterologist; Goals; HIV; Health; Immunity; Immunocompromised Host; Immunologics; Immunologist; Immunophenotyping; Individual; Infection; Inflammation; Inflammatory; Interleukin-6; Intervention; Intestines; Kwashiorkor; Kynurenine; Letters; Link; Liver diseases; Mediating; Mononuclear; Morbidity - disease rate; Mucosal Immunity; Obesity; Organism; Participant; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Positioning Attribute; Public Health; Recovery; Recruitment Activity; Recurrence; Relative (related person); Reporting; Research; Research Infrastructure; Research Personnel; Resolution; Risk; Safety; Sampling; Scientist; Specimen; Specimen Handling; Systemic disease; T-Cell Activation; T-Cell Proliferation; Therapeutic; Transplantation; Tryptophan; Visit; antiretroviral therapy; cohort; immune activation; immunoregulation; inflammatory marker; interdisciplinary approach; large bowel Crohn' s disease; microbial; microbial community; microbiome; mortality; peripheral blood; public health relevance; reconstitution; screening; trimethyloxamine

 DESCRIPTION (provided by applicant): Despite antiretroviral therapy (ART), a substantial number of HIV-infected individuals exhibit chronic systemic inflammation. Chronic inflammation is a major driver of HIV disease progression, excess morbidity (e.g. cardiovascular disease, accelerated liver disease) and mortality. Therefore, addressing persistent inflammation remains a major goal in restoring health of HIV-infected individuals. Our group reported that untreated and many treated HIV-infected individuals exhibit marked alterations in the gut microbiome compared with uninfected individuals, and the degree of dysbiosis correlates positively and strongly with peripheral blood markers of inflammation such as IL-6 and the ratio of kynurenine to tryptophan. Moreover, the bacterial communities overrepresented in HIV-infected individual are more likely to harbor the enzymatic pathway that catabolize tryptophan to kynurenine, a metabolite associated with HIV disease progression and suppresses T cell proliferation, in particular Th17 and Th22 cells, cells important in maintaining the mucosal barrier. Since fecal microbiome transplant (FMT) has been remarkably effective in reconstituting dysbiotic gut microbial communities as highlighted by its efficacy in treating patients with recurrent Clostridium difficile infection, the specific aims of this proposal are to manipulate the gut microbiome in ART treated HIV-infected individuals who are likely to harbor microbial dysbiosis and persistent inflammation by preferentially selecting participants with low CD4 or CD4:CD8 ratio less than one and elevated inflammatory biomarkers. In this study, we will determine the stability of the existing microbiome and use FMT 1) to determine engraftment and durability of the donor microbiome and its safety and 2) to examine whether this intervention can normalize systemic inflammatory markers and mucosal immunity. Stool and mucosal samples will enable high-resolution microbiome profiling, peripheral and gut mononuclear cells for immunophenotyping by flow cytometry, and plasma for assays of inflammatory biomarkers. In addition, asymptomatic HIV-infected ART suppressed individuals undergoing routine screening colonoscopy will be recruited to examine the effects of bowel cleansing on the microbial profile. Should this exploratory study reveal beneficial and sustained effects of microbiome modulation on host immunity and systemic inflammation, FMT or a consortium of bioactive organisms that can reconstitute the microbiome may provide benefit to individuals who exhibit excessive inflammation.

 描述（由申请人提供）：尽管进行了抗逆转录病毒治疗（ART），但仍有大量 HIV 感染者表现出慢性全身炎症。慢性炎症是 HIV 疾病进展、发病率过高（例如心血管疾病、加速性肝病）和慢性炎症的主要驱动因素。因此，解决持续性炎症仍然是恢复艾滋病毒感染者健康的一个主要目标，我们的研究小组报告说，未经治疗和许多接受治疗的艾滋病毒感染者的肠道微生物组表现出明显的改变。与未感染个体相比，生态失调的程度与外周血炎症标志物（例如 IL-6 和犬尿氨酸与色氨酸的比率）呈正相关且密切相关。将色氨酸分解为犬尿氨酸的酶途径，犬尿氨酸是一种与 HIV 疾病进展相关的代谢物，并抑制 T 细胞增殖，特别是 Th17 和 Th22 细胞，这些细胞在由于粪便微生物组移植 (FMT) 在重建失调的肠道微生物群落方面非常有效，其在治疗复发性艰难梭菌感染患者中的功效凸显了这一点，因此该提案的具体目标是在 ART 中操纵肠道微生物组。通过优先选择 CD4 较低或 CD4:CD8 比率小于 1 且治疗升高的参与者，可能存在微生物失调和持续炎症的 HIV 感染者在这项研究中，我们将现有微生物组的稳定性并使用 FMT 1) 确定供体微生物组的植入和持久性及其安全性，2) 确定这种干预是否可以使全身炎症标记物和粘膜免疫正常化。粪便和粘膜样本将能够进行高分辨率微生物组分析，通过流式细胞术对外周和肠道单核细胞进行免疫表型分析，并通过血浆进行炎症生物标志物分析。此外，如果这项探索性研究揭示微生物组调节对宿主免疫和全身炎症、FMT 或联合体的持续影响，将招募接受常规筛查结肠镜检查的无症状 HIV 感染 ART 抑制个体来检查肠道清洁对微生物特征的影响。可以重建微生物组的生物活性生物体可能会给表现出过度炎症的个体带来好处。