Microbiome targeted nutrition to improve immune function during critical illness

项目摘要 危重病患者普遍存在免疫抑制和骨髓功能障碍。短的 从长远来看，这将使本已脆弱的人口面临威胁生命的感染的额外风险。从长远来看， 免疫抑制可以以慢性危重疾病的形式持续存在，从而显著恶化功能 结果。有必要在危重病人的护理中及早恢复免疫功能，以避免 危重疾病的短期和长期有害后果。许多研究都试图这样做，但 通常都是失败的，仍然缺乏有针对性的治疗方法。这在一定程度上可能是由于缺乏考虑。 关于肠道微生物群在调节造血和免疫功能中的整体作用。 新出现的研究已经确定了免疫和肠道微生物群之间的基本联系。一个 大量的出版物表明，微生物群在不同的阶段塑造免疫系统，包括 在造血过程中。最近的小鼠研究表明，抗生素引起的生物失调损害 能促进造血，抑制骨髓功能。临床上，我们小组完成了一些第一次 基因组研究表明危重患者的微生物区系紊乱，可能是由于大量使用 抗生素。除抗生素外，大多数危重病人还依赖于肠内营养，这种营养塑造了他们的 微生物组。之前我们已经展示了人工肠内营养(AEN)，这是默认的，也是最常用的 为需要肠内营养的患者提供的配方会促进生物失调。相比之下，以高纤维植物为基础的肠道 营养具有良好的耐受性，可促进健康肠道厌氧菌的生长，改善预后。 在小鼠模型中。在这项建议中，未发表的数据表明，PBEN在缓解ABX方面优于AEN 导致淋巴细胞减少、贫血和中性粒细胞减少。我们还提供了证据表明危重病人被随机 TO PBEN组淋巴细胞数高于AEN组，中性粒细胞数低于AEN组。尽管如此，如何 抗生素和ABX诱导的骨髓抑制后饮食形态的造血从来没有直接过 测试过。在这里，我们将检验PBEN加速抗生素诱导的免疫恢复的假设 通过使用SCFA重新填充肠道来抑制骨髓抑制产生的共生体可以缓解 通过1)评估PBEN是否优于AEN来恢复髓系平衡 ABX诱导的骨髓恢复过程中的骨髓造血和淋巴细胞生成 抑制和2)检验从ABX诱导的骨髓加速免疫恢复的假设 对PBEN的抑制是由微生物产生的短链脂肪酸介导的。完成这些工作 AIMS将强调营养是以前被低估的改善免疫恢复的治疗目标 危重病人的名字。

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.