Tryptophan Co-Metabolism at the Host-Pathogen Interface

摘要

Microbes have evolved to exploit humans as a rich source of nutrients to support survival andreplication. 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, bybacteriaandfungi,commoncatabolicenzymesaresharedbybothhostandpathogens.Indoleamine2,3-dioxygenases (IDOs) catabolize Trp to kynurenines and are widely distributed from bacteriato metazoans. The evolutionary conservation of the kynurenine pathway may be linked tothe importance of the de novo synthesis of nicotinamide adenine dinucleotide (NAD+), towhich it ultimately leads, although additional functions of kynurenines are increasingly beingrecognized. Indeed, it is now clearly established that mammalian IDOs regulate infection anddrive 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 utilizeTrp via alternative pathways upon colonization of the host in a relationship that can be eithercommensalism or pathogenic. In these situations, the host and microbes are found to sharecommon substrates but the presence of dissimilar metabolic pathways may result in the generationof 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 Trpdegradation 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 whicha comprehensive assessment of the metabolic status is crucial to correctly evaluate pathologicalcolonization and drive the most appropriate therapeutic strategy.