Metabolites play a crucial role in regulating host physiology during infections. Metabolites can be produced by the host, obtained from the diet, or produced and modified by microbiota. These molecules act as signaling molecules that modulate the immune response and affect the outcome of infection. Understanding the role of metabolites is essential for unraveling the mechanisms underlying health and disease.In the first chapter of this thesis, I review the effects of metabolites on intestinal immunity. We provide an overview of the current understanding of the role of metabolites in regulating gut immune responses. This will lay the foundation for the subsequent chapters of this thesis, where I explore metabolomic alterations during COVID-19 infection and Long COVID, and the potential of metabolite-based therapies in the context of human health. At the start of the COVID-19 pandemic, it was unclear how COVID-19 pathogenesis alters host metabolites and what effects this may have on disease pathology. In the second chapter of this thesis, I show that COVID-19 is associated with changes in circulating metabolites. Specifically, COVID-19 infection results in shifts in circulating amino acid and amino acid derivatives including tryptophan and serotonin. Furthermore, patients with Long COVID exhibit persistently lower levels of tryptophan and serotonin compared to those who have recovered from acute COVID-19. Using mouse models, I elucidate the mechanisms behind decreased tryptophan and serotonin levels during acute and chronic viral infections as well as describe the consequences these metabolomic changes have on host physiology. In the third chapter, I review metabolite and microbiome-based therapies. These therapies, targeting specific metabolites or their pathways, show promise in treating metabolic disorders, inflammatory diseases, and infectious diseases. By modulating metabolite levels or activity, metabolite-based therapies offer targeted interventions to improve human health and treat diseases. Overall, understanding metabolomic changes during infections helps identify key metabolites, comprehend their impact on host physiology, and develop therapies to counteract these alterations. Metabolite-based therapies provide novel and targeted approaches for enhancing human health and addressing various diseases.