Host and Microbial Tryptophan Metabolic Profiling in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is associated with demyelination and neuronal loss. Over recent years, the immunological and neuronal effects of tryptophan (Trp) metabolites have been largely investigated, leading to the hypothesis that these compounds and the related enzymes are possibly involved in the pathophysiology of MS. Specifically, the kynurenine pathway of Trp metabolism is responsible for the synthesis of intermediate products with potential immunological and neuronal effects. More recently, Trp metabolites, originating also from the host microbiome, have been identified in MS, and it has been shown that they are differently regulated in MS patients. Here, we sought to discuss whether, in MS patients, a specific urinary signature of host/microbiome Trp metabolism can be potentially identified so as to select novel biomarkers and guide toward the identification of specific metabolic pathways as drug targets in MS.

Aryl Hydrocarbon Receptor Plasma Agonist Activity Correlates With Disease Activity in Progressive MS

“… 13 We and others have demonstrated the relevance of these dietary ligands in experimental models of CNS immunity, where their actions dampen proinflammatory T-cell responses 38 and limit CNS inflammation through AHR-driven mechanisms in astrocytes 9 and microglia. 7 In these lines, a recent study analyzed tryptophan metabolites in urine samples from patients with MS and controls to discover decreased levels in urine kynurine and a reduced kynurenine to tryptophan ratio in MS. 39 Although these and other metabolites might contribute to the reduction in AHR agonistic activity described in our study, concomitant modulation of antagonistic AHR ligands in MS cannot be excluded. Indeed, small increases in AHR antagonistic ligands could be masked by overlaying reductions in AHR activating ligand levels.…”

The Nerves to Conduct a Multiple Sclerosis Crime Investigation

“…Gut microbiota can metabolize dietary tryptophan to produce aryl hydrocarbon receptor (AHR) agonists that can limit CNS inflammation by acting on AHR receptors expressed by microglial cells [ 44 ]. Tryptophan metabolism has been of interest in autoimmunity research because metabolic products of the kynurenine pathway, which are used to metabolize tryptophan, are known to exert several effects on the immune system, including modulating immunotolerance [ 45 ]. Several studies have investigated the levels of kynurenines in MS patients or in the EAE mouse model, demonstrating that aberrant kynurenine pathway activity is associated with increased severity of disease [ 45 , 46 , 47 , 48 ].…”

Intestinal Dysbiosis and Tryptophan Metabolism in Autoimmunity

“…MS patients present a lower Kyn/Trp ratio in the urine ( 49 ) and cerebrospinal fluid ( 46 ), but a higher ratio in the serum ( 47 ), with a trend for reduced Trp and Kyn concentrations with disease progression ( 46 ). However, IDO expression was decreased in PBMCs of patients with stable disease compared to HCs, and was more drastically reduced along with the serum Kyn/Trp ratio in response to treatment ( 127 ).…”

“…Furthermore, bile acids are metabolized by the microbiota into secondary bile acids that also have immune modulatory activity (37). An altered distribution of tryptophan (Trp) metabolites has been identified in numerous autoimmune diseases (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49). Independently of endogenous host Trp metabolism, enzymes in the intestinal microbiota catabolize Trp to produce various metabolites (Figure 1) that play an important role in immune modulation and microbiota-host communication (50)(51)(52)(53).…”