UC San Diego

Mammalian metabolism and physiology are central to all aspects of health and disease. However, disruptions to homeostasis are more often the hallmarks of disease. Thus, aberrant metabolic states and physiological conditions are considered to be maladaptive and are overlooked for their role in host defense and the coevolution with microbes and pathogenic threats. Having co-evolved alongside microbes, it should be no surprise that hosts have evolved defense mechanisms founded in metabolic and physiological systems alongside our immune system. Here, we explore a novel role of the essential micronutrient iron which plays a dual role at the interface of infection and physiology. This thesis dissertation describes original work that examines how excess dietary iron modulates organismal energy balance through interfering with nutrient absorption. We found that negative energy balance in our model drives profound wasting of fat and lean energy depots and that iron-induced fat wasting protects lean energy stores from severe wasting in response to negative energy balance. Quite serendipitously, we found that iron supplementation alone, and iron-induced metabolic alterations mediate beneficial effects through two independent mechanisms in the context of infection. First, we found that dietary iron supplementation promotes resistance defenses during Citrobacter rodentium infection—which conflicts with the traditional role for iron defined by nutritional immunity. Iron-induced resistance prevented canonical colonic pathogenesis marked by region-specific expansion, induction of the innate inflammatory cascade and colitis. However, we found that the traditional hallmarks of C. rodentium-induced colitis that were previously assumed to correspond with inflammation emerge via two distinct stages of infection. Iron diet prevented expansion of C. rodentium and ensuing inflammatory cascades that are required to cause colon pathology. However, we found that iron-induced fat wasting and lipolysis is necessary to prevent non-inflammatory colon remodeling that occurs upon colonization with C. rodentium. Thus, we have identified a novel role for iron in promoting resistance defenses and modulating pathology. This work expands on the collective understanding of iron’s role in physiology and host defenses—providing mechanistic evidence to implicate iron in modulating a novel adipose-gut axis.