Microbes have evolved to exploit humans as a rich source of nutrients to support survival and replication. Although mammals and microbes may differ in their requirement for tryptophan (Trp), being an essential amino acid in the former and produced, with some exceptions, by bacteria and fungi, common catabolic enzymes are shared by both host and pathogens. Indoleamine 2,3-dioxygenases (IDOs) catabolize Trp to kynurenines and are widely distributed from bacteria to metazoans. The evolutionary conservation of the kynurenine pathway may be linked to the importance of the de novo synthesis of nicotinamide adenine dinucleotide (NAD+), to which it ultimately leads, although additional functions of kynurenines are increasingly being recognized. Indeed, it is now clearly established that mammalian IDOs regulate infection and drive immune tolerance by means of Trp deprivation and the generation of active metabolites, including kynurenines. An additional level of complexity can be envisaged when microbes utilize Trp via alternative pathways upon colonization of the host in a relationship that can be either commensalism or pathogenic. In these situations, the host and microbes are found to share common substrates but the presence of dissimilar metabolic pathways may result in the generation of metabolites, such as indoles or tryptamine that can cross-regulate each others metabolism. Here, we discuss the potential relevance of Co-Trp metabolism or alternative secondary pathways of Trp degradation in modulating host immune response and eventually the xenobiotic receptors (XRs), while regulating microbe fitness. These concepts are expected to open a novel scenario in which a comprehensive assessment of the metabolic status is crucial to correctly evaluate pathological colonization and drive the most appropriate therapeutic strategy.
Tryptophan Co-Metabolism at the Host-Pathogen Interface
Costantini C.;Bellet M. M.;Renga G.;Stincardini C.;Borghi M.;Pariano M.;Cellini B.;Romani L.;Zelante T.
2020
Abstract
Microbes have evolved to exploit humans as a rich source of nutrients to support survival and replication. Although mammals and microbes may differ in their requirement for tryptophan (Trp), being an essential amino acid in the former and produced, with some exceptions, by bacteria and fungi, common catabolic enzymes are shared by both host and pathogens. Indoleamine 2,3-dioxygenases (IDOs) catabolize Trp to kynurenines and are widely distributed from bacteria to metazoans. The evolutionary conservation of the kynurenine pathway may be linked to the importance of the de novo synthesis of nicotinamide adenine dinucleotide (NAD+), to which it ultimately leads, although additional functions of kynurenines are increasingly being recognized. Indeed, it is now clearly established that mammalian IDOs regulate infection and drive immune tolerance by means of Trp deprivation and the generation of active metabolites, including kynurenines. An additional level of complexity can be envisaged when microbes utilize Trp via alternative pathways upon colonization of the host in a relationship that can be either commensalism or pathogenic. In these situations, the host and microbes are found to share common substrates but the presence of dissimilar metabolic pathways may result in the generation of metabolites, such as indoles or tryptamine that can cross-regulate each others metabolism. Here, we discuss the potential relevance of Co-Trp metabolism or alternative secondary pathways of Trp degradation in modulating host immune response and eventually the xenobiotic receptors (XRs), while regulating microbe fitness. These concepts are expected to open a novel scenario in which a comprehensive assessment of the metabolic status is crucial to correctly evaluate pathological colonization and drive the most appropriate therapeutic strategy.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
