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.

项目概要免疫抑制和骨髓功能障碍在重症患者中普遍存在。短的从长远来看，这使本已脆弱的人群面临危及生命的感染的额外风险。长期，免疫抑制可以以慢性危重疾病的形式持续存在，从而显着恶化功能结果。在重症患者的护理中需要尽早挽救免疫功能，以避免危重疾病的短期和长期有害后果。许多研究都试图做到这一点，但总体上已经失败，并且仍然缺乏靶向治疗。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不可或缺的作用。新兴研究已经确定了免疫与肠道微生物组之间的基本联系。一个大量出版物表明微生物组在各个阶段塑造免疫系统，包括造血过程中。最近的小鼠研究表明抗生素引起的生态失调会损害造血并抑制骨髓功能。在临床上，我们小组完成了一些第一基因组研究表明危重患者的微生物群紊乱，可能是由于大量使用抗生素。除了抗生素外，大多数危重患者还依赖肠内营养，这决定了他们的病情微生物组。之前我们展示了默认且最常用的人工肠内营养（AEN）需要肠内营养的患者的配方会促进菌群失调。相比之下，高纤维植物肠内营养耐受性良好，促进健康共生肠道厌氧菌的生长，并改善结果在小鼠模型中。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、贫血和中性粒细胞增多。我们还提供了危重患者随机分组的证据与接受 AEN 的患者相比，接受 PBEN 的患者淋巴细胞计数较高，中性粒细胞计数较低。尽管如此，如何抗生素和饮食塑造 ABx 引起的骨髓抑制后的造血作用从未被直接研究过已测试。在这里，我们将检验 PBEN 加速抗生素诱导的免疫恢复的假设通过用短链脂肪酸 SCFA 重新填充肠道来抑制骨髓，产生共生体，从而减轻骨髓偏斜，通过 1) 评估 PBEN 在恢复稳态平衡方面是否优于 AEN ABx 诱导骨髓恢复期间骨髓中的骨髓生成和淋巴细胞生成抑制和 2) 检验加速 ABx 诱导骨髓免疫恢复的假设 PBEN 的抑制作用是通过微生物产生短链脂肪酸介导的。完成这些目标将强调营养作为以前被低估的改善免疫恢复的治疗目标的危重病人。