The role of DNA methylation in dysregulated monocyte immune responses during malnutrition and recovery

营养不良是由于热量或必需营养素摄入不足造成的，是一个持续存在的全球健康问题。在美国，超过1300万儿童面临与营养不良有关的粮食不安全问题（usda.gov）。营养不良与严重的发病率和死亡率有关，占五岁以下儿童死亡总数的45%以上。免疫力下降是一个主要的健康问题，因为传染病是营养不良儿童死亡的主要原因。儿童营养不良的长期后果是成年后肥胖、心脏代谢紊乱和癌症的发病率增加，其中免疫失调可能发挥重要作用。然而，营养不良中免疫缺陷的确切性质和潜在机制，特别是表观遗传学的作用，仍然不清楚。此外，大多数评估常见饮食干预措施治疗营养不良的有效性的研究都集中在关键的人体测量指标（身高，体重）上，但很少评估其他疾病风险标志物，如免疫功能。虽然免疫功能改变是儿童营养不良的一个公认后果，但其潜在机制尚不清楚。因此，迫切需要进行机制研究，以更好地了解营养不良和恢复的复杂生理学，以便设计更有效的饮食干预措施，改善短期和长期的健康结果。这项新的研究专门研究了单核细胞中DNA甲基化作为营养不良影响免疫反应的关键调节因子的作用。我们还将研究治疗饮食中常用的不同蛋白质来源如何改变这些机制。这项研究建立在我们自己的初步数据的基础上，这些数据显示了与小鼠不同饮食干预相关的免疫功能改变的差异。该研究的第一个目的是研究由低蛋白（5%蛋白质热量）饮食诱导的两周蛋白质营养不良如何影响断奶小鼠由细菌内毒素引起的单核细胞免疫反应。为了更好地理解机制，我们将探索改变的DNA甲基化模式和与单核细胞活动的关联。将通过全基因组亚硫酸氢盐测序评估DNA甲基化。在第二个目标中，我们将探索在诱导蛋白质营养不良两周后给予补充有小麦、牛奶或花生蛋白质的不同治疗饮食六周的功效。我们将确定不同处理饮食对免疫应答恢复的影响，并探索DNA甲基化作为饮食蛋白质对单核细胞对内毒素应答的差异效应的分子机制。这项研究将为未来的研究奠定基础，以了解减轻儿童营养不良对成人免疫功能和慢性疾病的长期影响的机会。

Malnutrition, resulting from insufficient intake of calories or essential nutrients, is a persistent global health problem. In the United States, over 13 million children face food insecurity linked to malnutrition (usda.gov). Malnutrition is associated with significant morbidity and mortality and is responsible for more than 45% of all deaths in children younger than five years. Decreased immunity is a major health concern as infectious diseases are the leading cause of mortality among malnourished children. The long-term consequences of childhood malnutrition are increased rates of obesity, cardiometabolic disorders and cancer in adulthood, in which immune dysregulation may play an important role. However, the exact nature of immunodeficiency in malnutrition and the underlying mechanisms, particularly the role of epigenetics, are still not understood. In addition, most studies evaluating the efficacy of common dietary interventions for treating malnutrition focus on key anthropometric measures (height, weight) but rarely assess other markers of disease risk such as immune function. While altered immune function is a well-established consequence of malnutrition in childhood, underlying mechanisms are unknown. Therefore, there is a critical need for mechanistic studies to better understand the complex physiology of malnutrition and recovery in order to design more effective dietary interventions that would improve both short- and long-term health outcomes. This novel study specifically examines the role of DNA methylation in monocytes as key regulator of the immune response impacted by malnutrition. We will also look at how different protein sources, commonly used in treatment diets alters these mechanisms. This study builds on our own preliminary data which showed differences in altered immune function associated with different dietary interventions in mice. The first aim of the study will investigate how two weeks of protein malnutrition, induced by a low protein (5% protein calories) diet, in weaning mice affects the monocyte immune response elicited by bacterial endotoxin. To better understand mechanisms, we will explore altered DNA methylation patterns and associations with monocytes activities. DNA methylation will be assessed by whole-genome bisulfite sequencing. In the second aim, we will explore the efficacy of different treatment diets supplemented with wheat, milk or peanut proteins administered for six weeks after a two-week period of induced protein malnutrition. We will determine the impact of the different treatment diets on the recovery of immune responses and explore DNA methylation as molecular mechanism underlying differential effects of dietary proteins on monocyte responses to endotoxin. The study will lay the foundation for future research to understand opportunities to mitigate the long-term effects of childhood malnutrition on adult immune function and chronic disease.