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

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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.