Microbiome targeted nutrition to improve immune function during critical illness

项目摘要 免疫抑制和骨髓功能障碍在危重患者中普遍存在。短 从长远来看，这使本已脆弱的人口面临更多的威胁生命的感染风险。从长远来看， 免疫抑制可以以慢性危重病的形式持续存在， 成果。有必要在重症患者的护理中早期抢救免疫功能，以避免 严重疾病的短期和长期不利后果。许多研究试图这样做，但 一般都失败了，仍然缺乏有针对性的治疗方法。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整体作用。 新兴的研究已经确定了免疫力和肠道微生物组之间的基本联系。一个 大量的出版物表明，微生物组在不同阶段塑造免疫系统，包括 在造血过程中。最近的鼠类研究表明抗生素诱导的生态失调损害 造血和抑制骨髓功能。在临床上，我们的团队完成了一些第一个 基因组研究说明了危重患者的微生物群紊乱，可能是由于自由使用 抗生素除了抗生素外，大多数重症患者还依赖肠内营养， 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促进了生态失调。相比之下，高纤维植物为基础的肠 营养耐受性良好，促进健康肠道厌氧菌的生长，并改善结果 在小鼠模型中。在该提案中，未发表的数据表明PBEN在缓解ABx方面优于AEN上级 诱发淋巴细胞减少症贫血和嗜中性粒细胞增多症我们还提供了证据表明，重症患者随机 PBEN组淋巴细胞计数高于AEN组，中性粒细胞计数低于AEN组。不过，怎么会 抗生素和饮食形状造血后ABx诱导的骨髓抑制从来没有直接 测试.在这里，我们将测试PBEN加速从免疫诱导的免疫恢复的假设。 通过用SCFA使肠道再生而产生骨髓抑制， 通过1）评估PBEN在恢复稳定状态平衡方面是否上级AEN， 从ABx诱导的骨髓中恢复期间骨髓中的骨髓生成和淋巴生成 抑制和2）测试加速从ABx诱导的骨髓中的免疫恢复的假设 PBEN的抑制作用是由短链脂肪酸的微生物产生介导的。完成这些 aims将强调营养作为以前未被充分认识的改善免疫恢复的治疗目标 危重病人的情况。

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.