Multi-omic evaluation of metabolic alterations in multiple sclerosis identifies shifts in aromatic amino acid metabolism

Fitzgerald, Kathryn C.; Smith, Matthew D.; Kim, Sol; Sotirchos, Elias S.; Kornberg, Michael D.; Douglas, Morgan; Nourbakhsh, Bardia; Graves, Jennifer; Rattan, Ramandeep; Poisson, Laila; Cerghet, Mirela; Mowry, Ellen M.; Waubant, Emmanuelle; Giri, Shailendra; Calabresi, Peter A.; Bhargava, Pavan

doi:10.1016/j.xcrm.2021.100424

Cited by 38 publications

(48 citation statements)

References 68 publications

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“…Among all DAMs, the most significant alterations were observed in the levels of amino acid metabolites; for instance, the relative levels of beta-alanyl-Larginine, L-glutamic acid, and L-valine were significantly increased, whereas those of L-tryptophan, L-leucine, L-isoleucine, L-tyrosine, L-phenylalanine, and cis-4-hydroxy-D-proline were significantly reduced in MS-affected patients compared with those in healthy subjects. Independent studies also showed similar changes in amino acid profiles in MSaffected subjects (102,103). The upregulation in the levels of L-glutamic acid and the downregulation in the levels of L-leucine and L-isoleucine were consistent with the results of previous studies (26,44).…”

Section: Discussionsupporting

confidence: 87%

Altered Plasma Metabolic Profiles in Chinese Patients With Multiple Sclerosis

Yang

Wu²,

Zhang

et al. 2021

Front. Immunol.

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Multiple sclerosis (MS) is an autoimmune disease that leads to the demyelination of nerve axons. An increasing number of studies suggest that patients with MS exhibit altered metabolic profiles, which might contribute to the course of MS. However, the alteration of metabolic profiles in Chinese patients with MS and their potential roles in regulating the immune system remain elusive. In this study, we performed a global untargeted metabolomics approach in plasma samples from 22 MS-affected Chinese patients and 21 healthy subjects. A total of 42 differentially abundant metabolites (DAMs) belonging to amino acids, lipids, and carbohydrates were identified in the plasma of MS patients and compared with those in healthy controls. We observed an evident reduction in the levels of amino acids, such as L-tyrosine, L-isoleucine, and L-tryptophan, whereas there was a great increase in the levels of L-glutamic acid and L-valine in MS-affected patients. The levels of lipid and carbohydrate metabolites, such as sphingosine 1-phosphate and myo-inositol, were also reduced in patients with MS. In addition, the concentrations of proinflammatory cytokines, such as IL-17 and TNF-α, were significantly increased, whereas those of several anti-inflammatory cytokines and chemokines, such as IL-1ra, IL-7, and MIP-1α, were distinctly reduced in the plasma of MS patients compared with those in healthy subjects. Interestingly, some DAMs, such as L-tryptophan and sphingosine 1-phosphate, showed an evident negative correlation with changes in the level of TNF-α and IL-17, while tightly positively correlating with altered concentrations of anti-inflammatory cytokines and chemokines, such as MIP-1α and RANTES. Our results revealed that altered metabolomic profiles might contribute to the pathogenesis and course of MS disease by modulating immuno-inflammatory responses in the peripheral system, which is essential for eliciting autoimmune responses in the central nervous system, thus resulting in the progression of MS. This study provides potential clues for developing therapeutic strategies for MS in the near future.

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Section: Discussionsupporting

confidence: 87%

Altered Plasma Metabolic Profiles in Chinese Patients With Multiple Sclerosis

Yang

Wu²,

Zhang

et al. 2021

Front. Immunol.

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“…Recently, Fitzgerald et al identified abnormalities in aromatic amino acid (AAA) metabolites using a multi-omic approach in patients with MS. A reduced quantity of AAA metabolites correlated with higher disability, and altered AAA metabolism was found in CSF- and serum-derived monocytes of patients with MS. These AAA metabolites may come from the gut microbiota 154 . Levels of butyrate- or indolelactate-producing bacteria are reduced in patients with MS 155 .…”

Section: Is Multiple Sclerosis a Metabolic Disease?mentioning

confidence: 99%

“…Modulating the metabolism of the AAA tryptophan, which is reduced in the serum and CSF of patients with MS 154 , 164 , 165 , could have therapeutic value. In vivo models showed reduced levels of tryptophan metabolites on both sides of the BBB (cortex and serum) during demyelination 166 .…”

Section: Is Multiple Sclerosis a Metabolic Disease?mentioning

confidence: 99%

“…The gut microbiome has been implicated in providing a pro-inflammatory environment that allows the emergence of activated myelin-specific T cells through bystander activation 297 . Through the release of metabolic products such as tryptophan derivatives that engage AHR, bacteria can regulate the cytokine milieu in the CNS and the function of neurons and glial cells 154 , 282 . Patients with MS have evidence of gut dysbiosis but studies have yielded heterogeneous results regarding overrepresentation and underrepresentation of bacterial species 155 , 298 .…”

Section: Tolerance Inductionmentioning

confidence: 99%

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Thinking outside the box: non-canonical targets in multiple sclerosis

Bierhansl

Hartung

Aktaş

et al. 2022

Nat Rev Drug Discov

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Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that causes demyelination, axonal degeneration and astrogliosis, resulting in progressive neurological disability. Fuelled by an evolving understanding of MS immunopathogenesis, the range of available immunotherapies for clinical use has expanded over the past two decades. However, MS remains an incurable disease and even targeted immunotherapies often fail to control insidious disease progression, indicating the need for new and exceptional therapeutic options beyond the established immunological landscape. In this Review, we highlight such non-canonical targets in preclinical MS research with a focus on five highly promising areas: oligodendrocytes; the blood–brain barrier; metabolites and cellular metabolism; the coagulation system; and tolerance induction. Recent findings in these areas may guide the field towards novel targets for future therapeutic approaches in MS.

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“…Studying metabolites in biofluids during disease states is emerging as a powerful approach, as distinct metabolite signature could be a potential biomarker for disease progression or predictive of the beneficial effect of DMTs in MS [ 154 ]. Few studies have outlined a distinct metabolic signature, including serum phospholipids [ 155 ], altered bile acid metabolism [ 156 ], abnormalities in aromatic amino acid metabolism [ 157 ], and pro-resolving lipid mediators in MS compared to healthy subjects, which could be developed as a biomarker for disease and/or novel therapy. Moreover, altered metabolite signature during disease relapse [ 158 , 159 ] could be developed as a metabolic biomarker for disease progression in MS.…”

Section: Biomarkers For a Future Bioinformatic Approachmentioning

confidence: 99%

Current and Future Biomarkers in Multiple Sclerosis

Yang

Hamade

et al. 2022

IJMS

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Multiple sclerosis (MS) is a debilitating autoimmune disorder. Currently, there is a lack of effective treatment for the progressive form of MS, partly due to insensitive readout for neurodegeneration. The recent development of sensitive assays for neurofilament light chain (NfL) has made it a potential new biomarker in predicting MS disease activity and progression, providing an additional readout in clinical trials. However, NfL is elevated in other neurodegenerative disorders besides MS, and, furthermore, it is also confounded by age, body mass index (BMI), and blood volume. Additionally, there is considerable overlap in the range of serum NfL (sNfL) levels compared to healthy controls. These confounders demonstrate the limitations of using solely NfL as a marker to monitor disease activity in MS patients. Other blood and cerebrospinal fluid (CSF) biomarkers of axonal damage, neuronal damage, glial dysfunction, demyelination, and inflammation have been studied as actionable biomarkers for MS and have provided insight into the pathology underlying the disease process of MS. However, these other biomarkers may be plagued with similar issues as NfL. Using biomarkers of a bioinformatic approach that includes cellular studies, micro-RNAs (miRNAs), extracellular vesicles (EVs), metabolomics, metabolites and the microbiome may prove to be useful in developing a more comprehensive panel that addresses the limitations of using a single biomarker. Therefore, more research with recent technological and statistical approaches is needed to identify novel and useful diagnostic and prognostic biomarker tools in MS.

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Multi-omic evaluation of metabolic alterations in multiple sclerosis identifies shifts in aromatic amino acid metabolism

Cited by 38 publications

References 68 publications

Altered Plasma Metabolic Profiles in Chinese Patients With Multiple Sclerosis

Altered Plasma Metabolic Profiles in Chinese Patients With Multiple Sclerosis

Thinking outside the box: non-canonical targets in multiple sclerosis

Current and Future Biomarkers in Multiple Sclerosis

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