Microbiome targeted nutrition to improve immune function during critical illness

微生物组靶向营养可改善危重疾病期间的免疫功能

基本信息

批准号：
10751673
负责人：
Mona Chatrizeh
金额：
$ 5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751673
关键词：
Adopted Anaerobic Bacteria Anemia Animals Antibiotics Bone Marrow Bone Marrow Suppression Bone marrow failure Cells Chronic Clinical Clinical Trials Critical Care Critical Illness Data Development Diet Dietary Fiber Disease Progression Emergency Situation Enteral Nutrition Equilibrium Fermentation Fiber Functional disorder Genomics Germ-Free Goals Growth Hematopoiesis Hematopoietic stem cells Immune Immune response Immune system Immunity Immunosuppression Impairment Infection Laboratories Lead Learning Life Link Lymphocyte Lymphocyte Count Lymphopenia Lymphopoiesis Mediating Mediator Mus Myelogenous Myelopoiesis Neutrophilia Operative Surgical Procedures Outcome Patients Plants Play Population Preparation Process Production Publications Randomized Recovery Reproducibility Research Risk Role Scientist Series Shapes Surgeon Testing Therapeutic Volatile Fatty Acids Vulnerable Populations Work clinically relevant cytokine dysbiosis experimental study fecal transplantation functional outcomes graduate student gut dysbiosis gut microbiome gut microbiota immune function immune health immunoregulation improved improved outcome metabolomics microbial microbiome microbiota mouse model neglect neutrophil nutrition protective effect secondary infection therapeutic target

项目摘要

Project Summary Immune suppression and bone marrow dysfunction are ubiquitous among critically ill patients. Short term, this places an already vulnerable population at additional risk of life-threatening infections. Long term, immune suppression can persist in the form of chronic critical illness which significantly worsens functional outcomes. There is a need to rescue immune function early in the care of critically ill patients to avoid detrimental short and long term consequences of critical illness. Many studies have attempted to do this but have generally failed, and targetable therapies are still lacking. This may be in part due to lack of consideration about the integral role of the gut microbiome in regulating hematopoiesis and immune function. Emerging research has identified fundamental links between immunity and the gut microbiome. An onslaught of publications have shown the microbiome shapes the immune system at various stages, including during hematopoiesis. Recent murine studies have illustrated antibiotic induced dysbiosis impairs hematopoiesis and suppresses bone marrow function. Clinically, our group completed some of the first genomic studies illustrating microbiota derangements in critically ill patients, likely as a result of liberal use of antibiotics. In addition to antibiotics, most critically ill patients rely on enteral nutrition which shapes their microbiome. Previously we have shown artificial enteral nutrition (AEN), the default and most commonly used formula for patients requiring enteral nutrition promotes dysbiosis. In contrast, high fiber plant based enteral nutrition is well tolerated, promotes the growth of healthy commensal gut anaerobes, and improves outcomes in murine models. In this proposal, unpublished data demonstrates PBEN is superior to AEN in mitigating ABx induced lymphopenia, anemia, and neutrophilia. We also provide evidence that critically ill patients randomized to PBEN have higher lymphocyte and lower neutrophil counts than those that received AEN. Still, how antibiotics and diet shape hematopoiesis after ABx induced bone marrow suppression has never been directly tested. Here, we will test the hypothesis that PBEN expedites immune recovery from antibiotic-induced bone marrow suppression via repopulation of the gut with SCFA producing commensals that mitigate myeloid skewing by 1) evaluating if PBEN is superior to AEN in restoring steady state balance between myelopoiesis and lymphopoiesis in the bone marrow during recovery from ABx induced bone marrow suppression and 2) testing the hypothesis that expedited immune recovery from ABx induced bone marrow suppression with PBEN is mediated by microbial production of short chain fatty acids. Completion of these aims will highlight nutrition as a previously underappreciated therapeutic target for improving immune recovery of critically ill patients.

项目摘要在重症患者中，免疫抑制和骨髓功能障碍无处不在。短的术语，这使本来已经脆弱的人群面临威胁生命的感染风险。长期，免疫抑制可以持续以慢性危害疾病的形式显着恶化结果。有必要在危重患者的护理中早期营救免疫功能以避免严重疾病的短期和长期后果有害。许多研究都试图这样做，但是通常失败了，仍然缺乏靶向疗法。这可能部分是由于缺乏考虑关于肠道微生物组在调节造血和免疫功能中的组合作用。新兴研究已经确定了免疫力与肠道微生物组之间的基本联系。一个出版物的猛烈攻击表明，微生物组在各个阶段形成了免疫系统，包括在造血期间。最近的鼠研究表明抗生素诱导的营养不良损害造血并抑制骨髓功能。临床上，我们的小组完成了一些第一个基因组研究说明了危重患者中微生物群的危险，这可能是由于自由使用而导致的抗生素。除抗生素外，大多数重症患者都依赖于肠内营养微生物组。以前我们已经显示了人工肠内营养（AEN），默认和最常用的需要肠内营养的患者配方奶粉会促进营养不良。相反，高纤维植物的肠内营养的耐受性良好，促进了健康的共生肠厌氧菌的生长，并改善了预后在鼠模型中。在此提案中，未发表的数据表明，PBEN在缓解ABX方面优于AEN 诱发淋巴细胞减少症，贫血和嗜中性粒细胞。我们还提供了证据表明重症患者随机生病与接受AEN相比，PBEN具有更高的淋巴细胞，中性粒细胞计数更低。但是，怎么样 ABX诱导的骨髓抑制后，抗生素和饮食形状造血作用从未直接直接测试。在这里，我们将检验以下假设，即PBEN会加快抗生素诱导的免疫恢复通过在SCFA产生缓解肠道的肠道中抑制骨髓抑制 1）评估PBEN在恢复稳态平衡时是否优于AE 从ABX诱导的骨髓恢复期间，骨髓中的骨髓骨髓和淋巴管抑制和2）测试假设的假设，该假说加快了ABX诱导的骨髓的免疫恢复用短链脂肪酸的微生物产生抑制PBEN。这些完成目的将重点介绍营养作为以前未经评估的治疗靶标，用于改善免疫恢复重病患者。