Altered tryptophan metabolism is associated with pediatric multiple sclerosis risk and course

Abstract

ObjectiveTo determine if altered tryptophan (Trp) metabolism is associated with MS risk or disease severity in children.MethodsParticipants with pediatric‐onset MS and clinically isolated syndrome (CIS) within 4 years of disease onset and healthy controls underwent collection of serum. Longitudinal disability and processing speed measures and relapse data were collected in cases. Global metabolomics were conducted in 69/67 cases/controls. Targeted Trp measurement was performed in a discovery group (82 cases, 50 controls) and a validation group (92 cases, 50 controls), while functional gut microbiome analysis was done in 17 cases. Adjusted logistic, linear and negative binomial regression and Cox‐proportional hazard models were used.ResultsUsing global metabolomics data, higher relative abundances of Trp and indole lactate, a known gut microbiota‐derived Trp metabolite, were associated with lower risk of MS. In cases, higher relative abundances of gut microbiota‐derived Trp metabolites were associated with lower disability and higher processing speed scores and higher relative abundance of kynurenine was associated with higher relapse rate. Using targeted tryptophan measures, in the discovery and validation groups, each 1 mcg/mL increase in serum Trp level was associated with 20% (95% CI: 4–34%) and 32% (95% CI: 16–44%) decrease in adjusted odds of having MS, respectively. A lower relative abundance of gut microbial genes involved in Trp catabolism was associated with higher relapse risk.InterpretationTrp metabolism by the gut microbiota and the kynurenine pathway may be relevant to the risk of MS in children as well as MS activity and severity.

Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation

“…Pediatric MS patients and HCs (n = 31 each) were recruited from the UCSF Pediatric MS Clinic. Participants underwent phlebotomy, and blood was processed and serum stored at -80°C until the time of metabolomics analyses (47).…”

Co-treatments to Boost IDO Activity and Inhibit Production of Downstream Catabolites Induce Durable Suppression of Experimental Autoimmune Encephalomyelitis

“…These points notwithstanding, our findings show that boosting kinetic flux through the Kyn pathway and manipulating the balance of alternative Trp metabolism pathways downstream of IDO have profound effects on immunologic responses to STING agonists that promote durable therapeutic responses in the EAE model. Abnormal levels of KA and QA were detected in serum of MS patients and abnormalities in Kyn pathway metabolism may be associated with clinical MS subtypes, and may serve as potential biomarkers of MS stage and progression (38,69,70). As we depict in the graphic hypothesis ( Figure 6) summarizing findings reported here, and in a previous study using the same model (10), the Kyn pathway has a complex role in immunologic and neurologic processes driving autoimmunity and comorbidities during EAE disease progression and responses to STING agonist treatments to alleviate EAE.…”

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

“…4). In pediatric patients with multiple sclerosis (MS), the relative abundance of TRP and indole lactate are negatively associated with the risk of MS. 156 In particular, a protective role of TRP metabolite components in CNS inflammation has been observed in an animal model of experimental autoimmune encephalomyelitis (EAE) that can replicate many of the characteristics of MS. TRP deficiency or specific deletion of AHR in astrocytes drives the recruitment of peripheral inflammatory cells to the brain and further potentiates the pathogenic and neurotoxic activities of astrocytes, thus amplifying local inflammation. 157,158 Microbially derived TRP metabolites can cross the BBB and further regulate the immune activity of microglia and astrocytes through AHR-driven mechanisms.…”