Sex Effects at the Ramparts: Nutrient- and Microbe-Mediated Regulation of the Immune-Metabolic Interface

The relationships between dietary compounds, derivative metabolites, and host metabolism and immunity are controlled by diverse molecular mechanisms. Essential contributions to these dynamics come from the community of microbes (the microbiome) inhabiting the human digestive tract. The composition and function of the microbiome are shaped by available nutrients, and reciprocally, these organisms produce an as yet poorly defined repertoire of molecules that communicate with the epithelial barrier and the mucosal immune system. We present evidence that diet-derived vitamins and lipids regulate immunity and metabolic function and highlight the diverse mechanisms through which these effects are impacted by sex. We discuss exciting new data emerging from studies using high-throughput sequencing technology, specialized mouse models, and bio-specimens, and clinical data from human subjects that have begun to reveal the complexity of these interactions. Also profiled in this chapter are the striking sex differences in pathways by which dietary nutrients and gut microbes modify metabolism, immunity, and immune- and inflammation-mediated diseases. Although the incidence, severity, and therapeutic responses of many autoimmune diseases differ by sex, the molecular mechanisms of these effects remain poorly understood.