Dynamic regulation of serum aryl hydrocarbon receptor agonists in MS

Abstract

Objective:Several factors influence the clinical course of autoimmune inflammatory diseases such as MS and inflammatory bowel disease. Only recently, the complex interaction between the gut microbiome, dietary factors, and metabolism has started to be appreciated with regard to its potential to modulate acute and chronic inflammation. One of the molecular sensors that mediates the effects of these environmental signals on the immune response is the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor with key functions in immune cells.Methods:In this study, we analyzed the levels of AHR agonists in serum samples from patients with MS and healthy controls in a case-control study.Results:We detected a global decrease of circulating AHR agonists in relapsing-remitting MS patients as compared to controls. However, during acute CNS inflammation in clinically isolated syndrome or active MS, we measured increased AHR agonistic activity. Moreover, AHR ligand levels in patients with benign MS with relatively mild clinical impairment despite longstanding disease were unaltered as compared to healthy controls.Conclusions:Collectively, these data suggest that AHR agonists in serum are dynamically modulated during the course of MS. These findings may guide the development of biomarkers to monitor disease activity as well as the design of novel therapeutic interventions for MS.

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

“…While metabolomics analyses have identified alterations in multiple metabolic processes in MS, these techniques have not been previously applied to pediatric MS and have not studied the tryptophan pathway as a whole 30. Reduced plasma levels of Trp and some of its metabolites have been reported in adult MS patients compared to healthy subjects and dynamic modulation of some of these metabolites in the course of the disease has been described,13, 31 but the study of Trp metabolism in the risk of MS and disease activity and severity is novel.…”

Detection of aryl hydrocarbon receptor agonists in human samples

“…It has recently been reported that AHR agonistic activity varies during the course of inflammatory diseases such as MS and inflammatory bowel disease (IBD), suggesting that changes in circulating AHR agonists reflect alterations in the commensal flora, uptake, degradation or metabolism of physiological AHR agonists 4 , 7 , 8 . Thus, the quantification of AHR agonists is of clinical interest.…”

“…HEK293, HepG2, and HEPA1 cells were used in the transient transfection system, as previously described 7 , 8 . In brief, 15,000 cells per well were plated in 96 well flat bottom plates.…”

“…Interestingly, we detected decreased AHR activation in MS brain lesions as indicated by the expression of the AHR target gene CYP1B1 , concomitant with decreased levels of AHR agonists in MS sera detected using a cell-based reporter assay and mass spectrometry 8 . Moreover, AHR agonistic activity in sera from MS patients was correlated both with disease activity and more severe stages of MS 7 . Collectively, these data identify AHR in astrocytes as a negative regulator of CNS inflammation.…”

Western lifestyle and immunopathology of multiple sclerosis

“…71 Moreover, serum levels of indoles and its metabolites are decreased in patients with MS. 71 However, a more recent study suggests a differential mechanism of regulation: AHR agonistic activity is increased during relapse episodes of MS and decreased during remission. 72 When discussing the role of nutrients in MS, we should carefully take into account not only a direct immunomodulatory role of diet but also its associated effects on microbiota composition and the development of obesity.…”